Pulmonary vascular resistance, collateral flow, and ventricular function in patients with a Fontan circulation at rest and during dobutamine stress.
The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood. Using an MRI catheterization technique, we performed a differential analysis of pulmonary vascular resistance and aortopulmonary collateral blood flow in conjunction with global ventricular pump function, myocontractility (end-systolic pressure-volume relation), and diastolic compliance (end-diastolic pressure-volume relation) in 10 patients with a Fontan circulation at rest and during dobutamine stress. Pulmonary and ventricular pressures were measured invasively and synchronized with velocity-encoded MRI-derived pulmonary and aortic blood flows and cine MRI-derived ventricular volumes. Pulmonary vascular resistance and end-systolic and end-diastolic pressure-volume relations were then determined. Aortopulmonary collateral flow was calculated as the difference between aortic and pulmonary flow. Compared to rest, dobutamine caused a small increase in mean pulmonary pressures (P<0.05). Collateral flow was significantly augmented (P<0.001) and contributed importantly to an increase in pulmonary flow (P<0.01). Pulmonary vascular resistance decreased significantly (P<0.01). Dobutamine did not increase stroke volumes significantly despite slightly enhanced contractility (end-systolic pressure-volume relation). Active early relaxation (τ) was inconspicuous, but the end-diastolic pressure-volume relation shifted upward, indicating reduced compliance. In patients with a Fontan circulation, aortopulmonary collateral flow contributes substantially to enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response to augmented cardiac output was adequate, but decreased diastolic compliance was identified as an important component of ventricular dysfunction.


Oleanolic acid regulates NF-κB signaling by suppressing MafK expression in RAW 264.7 cells.
Oxidative stress and inflammation are common to many pathological conditions. Defense mechanisms protect cells from oxidative stress, but can become over-activated following injury and inflammation. NF-κB and Nrf2 transcription factors regulate proinflammatory and antioxidant gene expression, respectively. Studies have shown that many natural dietary compounds regulate NF-κB and Nrf2, preventing inflammation and oxidative stress. Here, we report major compounds of Prunella vulgaris var. lilacina such as rosmarinic acid, oleanolic acid, ursolic acid and caffeic acid as a potential therapeutic for oxidative stress and inflammation. The major compounds exhibited high anti-inflammatory activity, inhibiting NO, PGE2 production, NF-κB expression and activating Nrf2 expression. In addition, we examined the effect of major compounds on MafK expression. Among the compounds, oleanolic acid significantly decreased MafK expression and MafK-mediated p65 acetylation. These findings suggest that oleanolic acid as NF-κB inhibitors can potentially be used in therapeutic applications for the treatment of oxidative stressnduced diseases.


Hard times and hurtful partners: how financial strain affects depression and relationship satisfaction of unemployed persons and their spouses.
The process linking unemployment and economic hardship to depression and marital or relationship satisfaction in couples was examined. Using structural equation modeling, the authors tested models in which financial strain and partners' symptoms of depression influence the behavioral exchange of the couples in terms of social support and social undermining and, in turn, the effects of support and undermining on relationship satisfaction and depressive symptoms. The analyses were based on longitudinal data from 815 recently unemployed job seekers and their spouses or partners. The results demonstrated that financial strain had significant effects on depressive symptoms of both partners, which in turn led the partner to withdraw social support and increase social undermining. Reduced supportive and increase undermining behaviors had additional adverse effects on satisfaction with the relationship and on depressive symptoms.


[Role of metabolism pathway interaction of formaldehyde and nitric oxide in the mechanism of their toxic effect. 2. Toxic effect of nitric oxide].
Toxic properties of NO in organism are realized under its hyperproduction and inhibition of the system of anti-oxidant protection as a result of complex chemical transformations, the transient metals, oxygen, superoxide and other radicals being their main participant. Here direct paths (through formation of nitrosil complexes with the gem and nongem iron) of the toxic action of NO and the path mediated by active forms of nitrogen are found, which disturb various biomolecules and subcellular component through the reactions of S- and N-nitrozation, nitration, oxidation, desamination and other reaction, cause metabolic disbalance and death of cells by the type of apoptosis or necrosis. A possible mechanism of the death of cells caused by NO was considered on the example of thymocytes. According to this mechanism one of early stages of this death is a decrease of the cell fund of AP, intensification of catabolism of adenine nucleotides and transformation of xanthine oxidoreductase from D-form (xanthine dehydrogenase) of O-forms (xantine oxidase) which catalizes formation of cytotoxic molecules of superoxide and hydroperoxide. This cytotoxic mechanism which includes transformation of xanthine oxidase system, is probably, universal and does not depend essentially on the starting factor.


Mitochondrial control region diversity of the houbara bustard Chlamydotis undulata complex and genetic structure along the Atlantic seaboard of North Africa.
The houbara bustard, Chlamydotis undulata, is a declining cryptic desert bird whose range extends from North Africa to Central Asia. Three subspecies are currently recognized by geographical distribution and morphology: C.u.fuertaventurae, C.u.undulata and C.u.macqueenii. We have sequenced 854 bp of mitochondrial control region from 73 birds to describe their population genetic structure with a particular sampling focus on the connectivity between C.u.fuertaventurae and C.u.undulata along the Atlantic seaboard of North Africa. Nucleotide and haplotypic diversity varied among the subspecies being highest in C.u.undulata, lowest in C.u.fuertaventurae and intermediate in C.u.macqueenii. C.u.fuertaventurae and C.u.undulata are paraphyletic and an average nucleotide divergence of 2.08% splits the later from C.u.macqueenii. We estimate that C.u.fuertaventurae and C.u.undulata split from C.u.macqueenii approximately 430 000 years ago. C.u.fuertaventurae and C.u.undulata are weakly differentiated (FST = 0.27, Nm = 1.3), indicative of a recent shared history. Archaeological evidence indicates that houbara bustards have been present on the Canary Islands for 130-170 000 years. However, our genetic data point to a more recent separation of C.u.fuertaventurae and C.u.undulata at around 20-25 000 years. Concordant archaeological, climatic opportunities for colonization and genetic data point to a scenario of: (i) initial colonization of the Canary Islands about 130 000 years ago; (ii) a period of secondary contact 19-30 000 years ago homogenizing any pre-existing genetic structure followed by; (iii) a period of relative isolation that persists today.


Endotoxin does not directly alter norepinephrine release or vasoactivity in dog pulmonary artery and portal vein.
The direct effect of Escherichia coli endotoxin on the release of norepinephrine (NE) and the contractile response consequent to the release of NE were studied in isolated, superfused segments of dog pulmonary artery and portal vein during resting conditions and during electrical stimulation (ES). High-pressure liquid chromatography with electrochemical detection was used to quantify the endogenous NE released and that remaining in the tissue after stimulation. Endotoxin (1 micrograms/ml and 10 micrograms/ml in superfusate) had no effect on the release of NE from either pulmonary artery or portal vein. Endotoxin also had no effect on vasoactivity in response to ES. Thus, in isolated pulmonary artery and portal vein, endotoxin, in the doses employed, does not directly affect release of NE from adrenergic nerve endings, nor does it affect the sequence of events that starts with transmitter-receptor interaction and ends with contraction of smooth muscle cells.


Lower COVID-19 Mortality in Patients with Type 2 Diabetes Mellitus Taking Dipeptidyl Peptidase-4 Inhibitors: Results from a Turkish Nationwide Study.
To investigate the effect of preexisting treatment with dipeptidyl peptidase-4 inhibitors (DPP-4is) on COVID-19-related hospitalization and mortality in patients with type 2 diabetes mellitus (T2DM). A multicenter, retrospective cohort study was conducted using patient data extracted from the Turkish National Electronic Database. All patients who tested positive for COVID-19 (PCR test) between 11 March through to 30 May 2020 were screened for eligibility (n = 149,671). Following exclusion of patients based on pre-determined inclusion criteria, patients with T2DM using a DPP-4i or glucose-lowering medications other than a DPP-4i were compared for mortality and hospitalization. The propensity score method was used to match age, gender, micro- and macrovascular complications, and medications in the two groups. Independent associates of mortality were analyzed using multivariable analysis on the whole T2DM population. A total of 33,478 patients with T2DM who tested postive for COVID-19 who met the inclusion criteria were included in the analysis. Median (interquartile range) age was 54 (22) years and 42.4% were male. Of these, 9100 patients using DPP-4is (n = 4550) or other glucose-lowering drugs (n = 4550) were matched in two groups. After matching, analysis revealed a lower mortality in the DPP-4i group (9.5 vs. 11.8%; p < 0.001). In the multivariable model, the use of DPP-4is (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.35-0.91; p = 0.02) was associated with lower mortality in the whole sample, while age, male gender, computed tomography finding of COVID-19, obesity, low glomerular filtration rate, and an insulin-based regimen also predicted increased risk of death. There was no association between the preexisting treatment with DPP-4is and COVID-19-related hospitalization in the matched analysis or multivariate model. The rate of admission to the intensive care unit and/or mechanical ventilation favored the DPP-4i group (21.7 vs. 25.2%; p = 0.001), although this association became saturated in the multivariate analysis (OR 0.65, 95% CI 0.39-1.08; p = 0.099). The results of this study demonstrate an association between DDP-4i use and reduced mortality in people with T2DM who tested PCR positive for COVID-19.


Gastric mucus of the guinea pig: proton carrier and diffusion barrier.
Proton transport with the gastric mucus was investigated in the guinea pig in vitro by use of three experimental series. In series I, pH profiles were obtained in the mucus and mucosa of a gastric explant with fine-tipped double-barreled microelectrodes. With a luminal pH of 1.8, pH increased across this layer to approximately 6 at the epithelial surface. Thickness of the gastric mucous gel layer increased continuously by 170 +/- 100 microns/h in the unstimulated and by 450 +/- 120 microns/h in the histamine-stimulated preparation (means +/- SD). In series II, fresh guinea pig gastric mucus was obtained from the gastric mucosa and titrated at 10 degrees C from pH 6.5 to 0.7, followed by an incubation period of 30 min at 37 degrees C. During this incubation period, a spontaneous acidic shift was observed, corresponding to a proton release from the mucus of 130 +/- 19 mM. This proton release could be blocked by the pepsin inhibitor pepstatin and was not observed when titrating down to only pH 3. Buffer values calculated as the mean slope of the titration curves in the pH range of 7 to 3 averaged 40 mM/pH unit. In series III, when titration was repeated with purified porcine mucin, no proton release was observed during incubation at pH 1.0, unless pepsinogen (375 U/ml) had been added before titration. Proton release during incubation at pH 1.0 and 37 degrees C in the presence of pepsinogen averaged 50 mM. The data suggest that protons secreted by the gastric mucosa are buffered by the continuously secreted mucus and transported, bound to the proteins of the mucus, toward the gastric lumen. During this transport, pepsinogen is converted within the mucus to pepsin. Pepsin modifies the buffering properties of the mucus, whereby protons are released from the protein binding. Thus the mucus forms a vehicle for proton transport toward the gastric lumen while, at the same time, constituting a diffusion barrier to prevent proton backdiffusion toward the gastric epithelium.


Agonist-induced beta-adrenergic receptor internalization on intact human mononuclear leukocytes: effect of temperature of mononuclear leukocyte separation.
The hydrophilic ligand 3H-CGP 12177 was used to measure beta-adrenergic receptors on intact human mononuclear leukocytes (MNLs). A single homogeneous class of receptor sites was found, with KD value of 0.71 +/- 0.04 nmol/L and Bmax of 3.0 +/- 0.4 fmol/10(6) cells (mean +/- SEM; n = 12). The receptor affinity (KD) and density (Bmax) were similar when measured on MNLs, purified lymphocytes, and a T-lymphocyte-enriched population from the same individual. Preincubation of intact MNLs with 1 mumol/L isoproterenol at 37 degrees C for 20 minutes reduced the number of surface receptors, measured by 3H-CGP 12177 binding at 4 degrees C for 20 hours, by approximately 70% (receptor internalization) without affecting KD. This effect was reversible, and surface receptors completely reappeared when binding was investigated at 37 degrees C for 40 minutes. Receptor internalization was similar when either isolated MNLs or whole blood was incubated with isoproterenol. Agonist-induced receptor internalization was stable during MNL isolation from whole blood at 4 degrees C but was partially or completely lost from MNLs prepared at 20 degrees C.


[Status of central hemodynamics in persons with a history of diagnosed primary rheumocarditis in childhood].
Ninety-eight subjects with a diagnosis of primary rheumocarditis made at a pediatric clinic in childhood were examined for the central hemodynamics by tetrapolar chest rheography. Based on a clinical and instrumental study rheumatic heart disease was diagnosed in 3 subjects; in 37 subjects, no heart pathology was recognized; myocarditic cardiosclerosis was diagnosed in 22, obesity in 20, and neurocirculatory dystonia of the cardial type in 16 subjects. The data obtained point to the overdiagnosis of rheumatic fever.


Integration of transcript expression, copy number and LOH analysis of infiltrating ductal carcinoma of the breast.
A major challenge in the interpretation of genomic profiling data generated from breast cancer samples is the identification of driver genes as distinct from bystander genes which do not impact tumorigenesis. One way to assess the relative importance of alterations in the transcriptome profile is to combine parallel analyses that assess changes in the copy number alterations (CNAs). This integrated analysis permits the identification of genes with altered expression that map within specific chromosomal regions which demonstrate copy number alterations, providing a mechanistic approach to identify the 'driver genes'. We have performed whole genome analysis of CNAs using the Affymetrix 250K Mapping array on 22 infiltrating ductal carcinoma samples (IDCs). Analysis of transcript expression alterations was performed using the Affymetrix U133 Plus2.0 array on 16 IDC samples. Fourteen IDC samples were analyzed using both platforms and the data integrated. We also incorporated data from loss of heterozygosity (LOH) analysis to identify genes showing altered expression in LOH regions. Common chromosome gains and amplifications were identified at 1q21.3, 6p21.3, 7p11.2-p12.1, 8q21.11 and 8q24.3. A novel amplicon was identified at 5p15.33. Frequent losses were found at 1p36.22, 8q23.3, 11p13, 11q23, and 22q13. Over 130 genes were identified with concurrent increases or decreases in expression that mapped to these regions of copy number alterations. LOH analysis revealed three tumors with whole chromosome or p arm allelic loss of chromosome 17. Genes were identified that mapped to copy neutral LOH regions. LOH with accompanying copy loss was detected on Xp24 and Xp25 and genes mapping to these regions with decreased expression were identified. Gene expression data highlighted the PPARα/RXRα Activation Pathway as down-regulated in the tumor samples. We have demonstrated the utility of the application of integrated analysis using high resolution CGH and whole genome transcript analysis for detecting driver genes in IDC. The high resolution platform allowed a refined demarcation of CNAs and gene expression profiling provided a mechanism to detect genes directly impacted by the CNA. This is the first report of LOH integrated with gene expression in IDC using a high resolution platform.


Tree leaves extraction in natural images: comparative study of preprocessing tools and segmentation methods.
In this paper, we propose a comparative study of various segmentation methods applied to the extraction of tree leaves from natural images. This study follows the design of a mobile application, developed by Cerutti et al. (published in ReVeS Participation--Tree Species Classification Using Random Forests and Botanical Features. CLEF 2012), to highlight the impact of the choices made for segmentation aspects. All the tests are based on a database of 232 images of tree leaves depicted on natural background from smartphones acquisitions. We also propose to study the improvements, in terms of performance, using preprocessing tools, such as the interaction between the user and the application through an input stroke, as well as the use of color distance maps. The results presented in this paper shows that the method developed by Cerutti et al. (denoted Guided Active Contour), obtains the best score for almost all observation criteria. Finally, we detail our online benchmark composed of 14 unsupervised methods and 6 supervised ones.


Spinal cord MRI using multi-array coils and fast spin echo. II. Findings in multiple sclerosis.
We performed MRI of brain and spinal cord on 80 patients with multiple sclerosis (MS). Using multi-array coils and fast spin echo, 139 intrinsic lesions were identified in 59 patients (74%). Lesions were more common in the cervical than in the thoracic cord. Cross-sectional areas of the cord, measured from axial images at four levels, showed atrophy in 40%. Clinical disability correlated with cord atrophy but not with cord lesion load. These results show that the use of multi-array coils and fast spin echo allows rapid and sensitive detection of spinal cord lesions in MS and that the cord is involved in the majority of patients. A lack of association between cord lesions and disability may relate to limitations in MR resolution but also suggests that the mechanisms of disability in MS are complex and multifactorial.


Medical approaches to prevention of restenosis after coronary angioplasty.
Although initial success rates for coronary angioplasty have improved, the rate of restenosis within 6 months of the procedure has persisted at 30 to 40%. The relation of restenosis to initial success, recurrence of symptoms and risk factors suggests that high grade or total lesions, long lesions, lesions in the proximal left anterior descending artery or in saphenous grafts, and the absence of intimal dissection after angioplasty are associated with an increased risk of restenosis. Unstable angina, male sex and diabetes are clinical factors associated with a greater risk of restenosis. Pathologic specimens suggest that plaque splitting and disruption are found acutely after angioplasty, but that restenosis occurs as an excessive reparative, proliferative response of smooth muscle cells leading to recurrent luminal narrowing. A prospective analysis of therapeutic interventions to prevent restenosis, such as administering antiplatelet and lipid-lowering agents, intensive diabetic therapy and administration of calcium antagonists, is proposed. Problems with timing of studies, design and sample size are considered. Current recommendations for anti-restenosis therapy include antiplatelet therapy before and after angioplasty, administration of heparin in some patients and intensive risk factor intervention for the 6 months after the procedure.


Isolation and characterization of the outer membrane of Borrelia hermsii.
The outer membrane of Borrelia hermsii has been shown by freeze-fracture analysis to contain a low density of membrane-spanning outer membrane proteins which have not yet been isolated or identified. In this study, we report the purification of outer membrane vesicles (OMV) from B. hermsii HS-1 and the subsequent identification of their constituent outer membrane proteins. The B. hermsii outer membranes were released by vigorous vortexing of whole organisms in low-pH, hypotonic citrate buffer and isolated by isopycnic sucrose gradient centrifugation. The isolated OMV exhibited porin activities ranging from 0.2 to 7.2 nS, consistent with their outer membrane origin. Purified OMV were shown to be relatively free of inner membrane contamination by the absence of measurable beta-NADH oxidase activity and the absence of protoplasmic cylinder-associated proteins observed by Coomassie blue staining. Approximately 60 protein spots (some of which are putative isoelectric isomers) with 25 distinct molecular weights were identified as constituents of the OMV enrichment. The majority of these proteins were also shown to be antigenic with sera from B. hermsii-infected mice. Seven of these antigenic proteins were labeled with [3H]palmitate, including the surface-exposed glycerophosphodiester phosphodiesterase, the variable major proteins 7 and 33, and proteins of 15, 17, 38, 42, and 67 kDa, indicating that they are lipoprotein constituents of the outer membrane. In addition, immunoblot analysis of the OMV probed with antiserum to the Borrelia garinii surface-exposed p66/Oms66 porin protein demonstrated the presence of a p66 (Oms66) outer membrane homolog. Treatment of intact B. hermsii with proteinase K resulted in the partial proteolysis of the Oms66/p66 homolog, indicating that it is surface exposed. This identification and characterization of the OMV proteins should aid in further studies of pathogenesis and immunity of tick-borne relapsing fever.


Discontinuation of cardiac implantable electronic device therapy after transvenous lead extraction.
Patients with cardiac implantable electronic devices (CIEDs) may no longer be eligible for continued therapy. The study aimed to assess the circumstances under which CIED reimplantation may not be necessary after transvenous lead extraction (TLE). A retrospective analysis of 3646 TLE procedures was performed with assessment of indications for device reimplantation. Reimplantation was not performed immediately after TLE in 169 (4.6%) and, in long-term follow-up, in 146 (4.0%) of patients. No further need for CIED reimplantation was mostly associated with establishment of stable sinus rhythm (2.4%), conversion of sinus node dysfunction to chronic atrial fibrillation (AF; 1.4%), or improvement in left ventricular ejection fraction (LVEF) (0.9%). Independent prognostic factors were in the pacing groups: LVEF (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.05; P <0.001), AF (OR, 3.8; 95% CI, 2.4-15.7; P <0.001), patients' age during first CIED implantation (OR, 0.97; 95% C, 0.96-0.98; P <0.001), and New York Heart Association (NYHA) class (OR, 0.616; 95% CI, 0.43-0.86; P <0.01); in the cardioverter-defibrillator group: LVEF (OR, 1.06; 95% CI, 1.04-1.09; P <001). Non-reimplanted patients had more complex procedures and more frequent complications, but survival after TLE was better in this group of patients. Reassessment of the need for continuation of CIED therapy should be considered in all patients following lead extraction and also before planned device replacement as TLE delay increases implant duration, complexity, and procedural risk. The predictors of non-reimplantation are a younger age during the first CIED implantation, lower NYHA class, presence of AF, and higher LVEF in pacemaker carriers, and, in the defibrillator group, only higher LVEF. A decision not to reimplant does not negatively affect the long-term prognosis.


Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration.
To evaluate the efficacy of transpupillary thermotherapy for the treatment of occult subfoveal choroidal neovascularization (CNV) in patients with age-related macular degeneration. A retrospective, noncomparative case series. Sixteen eyes of 15 consecutive patients who presented with occult subfoveal choroidal neovascularization secondary to age-related macular degeneration. After informed consent was obtained, 16 eyes of 15 patients were treated with transpupillary thermotherapy. All patients underwent pretreatment fluorescein angiography and were deemed untreatable by the Macular Photocoagulation Study standard. Transpupillary thermotherapy was delivered using a diode laser at 810 nm. A variable spot size of 1.2 mm, 2.0 mm, or 3.0 mm was used depending on the size of CNV. The diode laser was delivered through a contact lens, and treatment was initiated in one spot for 60 seconds' duration at a power range between 360 and 1000 mW. The end point was an area of no visible color change to a light-gray appearance. In all eyes, outcome was assessed by Snellen chart visual acuity and clinical examination. In 10 of 16 eyes, preoperative and postoperative fluorescein angiography and optical coherence tomography were available. In the remaining 6 of 16 eyes, exudation was measured by postoperative clinical examination alone. Three eyes (19%) showed a two-or-more-line improvement in visual acuity over a period of 6 to 25 months. Mean follow-up was 13 months. Visual acuity remained stable (no change or one-line improvement) in nine treated eyes (56%). The remaining four eyes (25%) showed a decline (equal to one-line worsening or greater) in visual acuity. Fifteen eyes (94%) demonstrated decreased exudation on fluorescein angiography, optical coherence tomography, and/or clinical examination. Transpupillary thermotherapy shows no deleterious side effects in treating occult subfoveal choroidal neovascularization. A randomized, prospective study is necessary to evaluate treatment efficacy.


Airflow limitation during respiratory syncytial virus lower respiratory tract infection predicts recurrent wheezing.
Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is frequently followed by recurrent wheezing. Thus far no clinical risk factors have been identified to predict which infants will have wheezing episodes subsequent to RSV LRTI. To determine clinical predictors for airway morbidity after RSV LRTI. In a 1-year follow-up study we investigated the predictive value of auscultatory findings characteristic of airflow limitation (wheezing) during RSV LRTI for subsequent airway morbidity. Clinical characteristics, including the presence or absence of signs of airflow limitation, of hospitalized infants with RSV LRTI were prospectively recorded during 2 winter epidemics. During a 1-year follow-up period parents of 130 infants recorded daily airway symptoms. Recurrent wheezing defined as > or = 2 episodes of wheezing. Signs of airflow limitation during RSV LRTI were absent in 47 (36%) infants and present in 83 (64%) infants. Recurrent wheezing was recorded in 10 (21%) infants without signs of airflow limitation and in 51 (61%) with signs of airflow limitation during initial RSV LRTI (relative risk, 0.29, P < 0.001). In a multiple logistic regression model, airflow limitation during initial RSV LRTI proved independent from other clinical parameters, including age, parental history of asthma and smoke exposure. A sign of airflow limitation during RSV LRTI is the first useful clinical predictor for subsequent recurrent wheezing.


Modeling the localized-to-itinerant electronic transition in the heavy fermion system CeIrIn5.
We address the fundamental question of crossover from the localized to the itinerant state of a paradigmatic heavy fermion material: CeIrIn5. The temperature evolution of the one-electron spectra and the optical conductivity are predicted from first-principles calculation. The buildup of coherence in the form of a dispersive many-body feature is followed in detail, and its effects on the conduction electrons of the material are revealed. We find multiple hybridization gaps and link them to the crystal structure of the material. Our theoretical approach explains the multiple peak structures observed in optical experiments and the sensitivity of CeIrIn5 to substitutions of the transition metal element and may provide a microscopic basis for the more phenomenological descriptions currently used to interpret experiments in heavy fermion systems.


The effect of trimethoprim on potassium and uric acid metabolism in normal human subjects.
Trimethoprim used in combination with other antibiotics, has been implicated in causing hyperkalemia and hypouricemia in patients with acquired immune deficiency syndrome (AIDS). In experimental animal models, trimethoprim has been demonstrated to block sodium channels and Na+-K+-ATPase in the distal nephron and thus impair potassium excretion. Although the data from the experimental models suggest that trimethoprim reduces urinary potassium excretion, the retrospective clinical studies have confounding factors that prevent a rigorous demonstration that the hyperkalemia and hypouricemia are due solely to the effects of trimethoprim on solute excretion. The purpose of this study was to evaluate the effect of trimethoprim on potassium and uric acid balance in normal human subjects. Five normal human subjects were admitted to the general clinical research center and placed on a fixed metabolic diet. After a 4-day control period, the subjects were given trimethoprim (15 mg/kg/day) orally for 5-7 days followed by a 4-day recovery period. Free-flow blood samples and 24-hour urine collections were obtained daily. Treatment with trimethoprim resulted in a significant increase in plasma potassium concentration (4.5 +/- 0.1 versus 3.7 +/- 0.1 mmol/l, p < 0.005) and significant decrease in serum uric acid concentration (3.8 +/- 0.4 versus 5.6 +/- 0.5 mg/dl, p < 0.001). Treatment with trimethoprim significantly increased the urinary excretion of uric acid, but did not significantly decrease potassium excretion during the 7-day treatment period. There was, however, a significant decrease in potassium excretion observed during the first 48 hours of trimethoprim treatment. In one subject where repeat studies were performed using different dosages, the effect on potassium and uric acid levels appeared to be dose-dependent. Trimethoprim increases plasma potassium concentration probably by reducing urinary potassium excretion. Trimethoprim decreases serum uric acid levels by augmenting urinary uric acid excretion. This uricosuric effect may be due to the ability of trimethoprim to impair urate reabsorption by the urate-anion exchanger in the proximal tubule.


Localization of GABAA receptor subunits alpha 1, alpha 3, beta 1, beta 2/3, gamma 1, and gamma 2 in the salamander retina.
Electrophysiological studies have demonstrated that gamma-aminobutyric acid receptors type A (GABA(A)) mediate important information processing in the retinas of salamander and other vertebrates. The pharmacology and physiology of GABA(A) receptors depend on their subunit composition. We studied the localization of GABA(A) receptor subunit isoforms alpha(1), alpha(3), beta(1), beta(2/3) (antibody BD-17 and 62-3G1), gamma(1), and gamma(2) in salamander retina with immunocytochemical methods. All three beta-subunit antibodies labeled similarly in the outer retina, especially the inner segments and synaptic terminals of rod photoreceptors (identified with protein kinase C). Somatic labeling was observed in cell bodies of some horizontal cells, bipolar cells, amacrine cells, and cells in the ganglion cell layer (GCL). Puncta were present throughout the inner plexiform layer (IPL) for beta(1) and 62-3G1, but not for BD-17. alpha(1)-immunoreactivity (IR) stained a population of presumed OFF rod-dominated bipolar cells, including dendrites, soma, and axon terminals in the distal IPL. A subtype of GABAergic amacrine cell also expressed alpha(1)-IR, with puncta sparsely distributed at the distal and proximal margins of the IPL. Both the OPL and IPL were labeled throughout for alpha(3)-IR, as opposed to the narrow distribution of alpha(1)-IR in the IPL, suggesting that the two alpha-subunits are localized at different synaptic sites. Punctate gamma(1)-IR was observed in the OPL and IPL, whereas gamma(2) was most prominent in cone photoreceptors (identified with calbindin), including the terminal telodendria, in cell bodies of some horizontal cells, amacrine cells, cells in the GCL, and less intensely in the IPL. In addition, several subunits were present in Müller cells. The differential labeling suggests the existence of GABA(A) receptor subtypes with different subunit compositions that mediate multiple GABAergic functions in salamander retina.


[Activities of the liver microsome reductases in adult and aged rats during stress].
The influence of 0.01% sodium dodecyl sulphate, 1.5 and 6.0 M urea and 0.03 M hydrogen peroxide to the NAD(P)H: 2,6 dichlorphenolindophenol reductase activity in livers of adult and old Wistar rats during immobilizing stress was interested. Obtained results indicate that the NADPH--dependent reductase is more resistant to modulating effect of sodium dodecyl sulphate, hydrogen peroxide and urea than NADH-dependent enzyme. The significant decrease of NADH: 2.6 dichlorphenolindophenol reductase sensitivity to the action of all studied modulators occurs in old rats. The similar changes appears in the adult rats liver during stress. The old rats immobilization is accompanied by a decrease of this enzyme activity and the reduction of the influence of all studied modulators to NADH: 2.6 dichlorphenolindophenol reductase as compared with adult ones. These changes in the activity and properties of microsomal NADH: 2,6 dichlorphenolindophenol reductase promote more pronounced decrease of the substrate hydroxylation in the liver of old rats during stress compared to adult ones.


[Exposure to multiresisant tuberculosis: study and follow-up of nine children].
A world increase in multidrug-resistant tuberculosis (MDR-TB) has been reported over the last few years. A larger number of diagnoses are being seen in Spain, due to the increase of immigration from high endemic TB countries. Articles published on this are anecdotal in children, and there is no clear directives for treatment of MDR-TB, or latent tuberculosis infection (ITBL) or on prophylaxis after exposure to active pulmonary MDR-TB. We present the initial management and progression of nine children after close contact exposure to an Ecuadorian woman diagnosed with active pulmonary TB, resistant to Isoniazid, Rifampicin and Pyrazinamide.


Conducting carbon wires in ordered, nanometer-sized channels.
The encapsulation of graphite-type carbon wires in the regular, 3-nanometer-wide hexagonal channels of the mesoporous host MCM-41 is reported. Acrylonitrile monomers are introduced through vapor or solution transfer and polymerized in the channels with external radical initiators. Pyrolysis of the intrachannel polyacrylonitrile results in filaments whose microwave conductivity is about 10 times that of bulk carbonized polyacrylonitrile. The MCM host plays a key role in ordering the carbon structure, most likely through the parallel alignment of the precursor polymer chains in the channels. The fabrication of stable carbon filaments in ordered, nanometer-sized channels represents an important step toward the development of nanometer electronics.


Developmental uterine anomalies in cats and dogs undergoing elective ovariohysterectomy.
To describe the characteristics and frequency of gross uterine anomalies in cats and dogs undergoing elective ovariohysterectomy. Prospective and retrospective case series. 53,258 cats and 32,660 dogs undergoing elective ovariohysterectomy at 26 clinics in the United States and Canada during 2007. Clinics prospectively reported gross anomalies and submitted tissues from abnormal reproductive tracts identified during surgery. Records from a feral cat spay-neuter clinic were evaluated retrospectively. Suspected congenital anomalies of the uterus were identified in 0.09% (49/53,258) of female cats and 0.05% (15/32,660) of female dogs. Uterine anomalies identified included unicornuate uterus (33 cats and 11 dogs), segmental agenesis of 1 uterine horn (15 cats and 3 dogs), and uterine horn hypoplasia (1 cat and 1 dog). Ipsilateral renal agenesis was present in 29.4% (10/34) of cats and 50.0% (6/12) of dogs with uterine anomalies in which kidneys were evaluated. Mummified ectopic fetuses were identified in 4 cats with uterine anomalies. Both ovaries and both uterine tubes were present in most animals with uterine anomalies. Urogenital anomalies were twice as common in cats as in dogs. Identification of uterine developmental anomalies in dogs and cats should trigger evaluation of both kidneys and both ovaries because ipsilateral renal agenesis is common, but both ovaries are likely to be present and should be removed during ovariohysterectomy.


Hb zoeterwoude [beta23(B5)Val-->Ala)]: a new beta-globin variant found in association with erythrocytosis.
We describe the characterization of a new hemoglobin (Hb) variant found in a 77-year-old Dutch woman, suspected of hypoxia-mediated erythrocytosis. The typical blood parameters (Hb 17.3 g/dL; PCV 0.525 L/L; RBC 5.82 x 10(12)/L) could not be explained by any of the pathological or physiological conditions causing erythrocytosis. The patient was preventively phlebotomized because of intermittent claudication and erythrocytosis. At the hematological and biochemical levels, no anemia or hemolysis were present and no abnormal Hb fractions were detectable on alkaline electrophoresis or high performance liquid chromatography (HPLC). Molecular analysis revealed intact alpha-globin genes and a heterozygosity for a GTT-->GCT transition at codon 23 of the beta-globin gene, causing a Val-->Ala amino acid substitution. The P50 measured in full blood indicated that this mutant has an elevated oxygen affinity. This is the fourth single nucleotide substitution at codon 23 of the beta gene and the second associated with erythrocytosis. Because the family was not available for investigation no information was obtained as to whether the mutation represents a de novo event or was inherited, and might be a more common cause of erythrocytosis in Dutch patients. Considering the relatively high frequency of beta-thalassemia (thal) in the large allochthonous population in The Netherlands, combinations of Hb Zoeterwoude and beta-thal traits may lead to hemizygosity, with severe hypoxia and erythrocytosis from a few months after birth.


Transcriptional profile of breast muscle in heat stressed layers is similar to that of broiler chickens at control temperature.
In recent years, the commercial importance of changes in muscle function of broiler chickens and of the corresponding effects on meat quality has increased. Furthermore, broilers are more sensitive to heat stress during transport and at high ambient temperatures than smaller egg-laying chickens. We hypothesised that heat stress would amplify muscle damage and expression of genes that are involved in such changes and, thus, lead to the identification of pathways and networks associated with broiler muscle and meat quality traits. Broiler and layer chickens were exposed to control or high ambient temperatures to characterise differences in gene expression between the two genotypes and the two environments. Whole-genome expression studies in breast muscles of broiler and layer chickens were conducted before and after heat stress; 2213 differentially-expressed genes were detected based on a significant (P < 0.05) genotype × treatment interaction. This gene set was analysed with the BioLayout Express3D and Ingenuity Pathway Analysis software and relevant biological pathways and networks were identified. Genes involved in functions related to inflammatory reactions, cell death, oxidative stress and tissue damage were upregulated in control broilers compared with control and heat-stressed layers. Expression of these genes was further increased in heat-stressed broilers. Differences in gene expression between broiler and layer chickens under control and heat stress conditions suggest that damage of breast muscles in broilers at normal ambient temperatures is similar to that in heat-stressed layers and is amplified when broilers are exposed to heat stress. The patterns of gene expression of the two genotypes under heat stress were almost the polar opposite of each other, which is consistent with the conclusion that broiler chickens were not able to cope with heat stress by dissipating their body heat. The differentially expressed gene networks and pathways were consistent with the pathological changes that are observed in the breast muscle of heat-stressed broilers.


The NCCR TransCure: An Incubator for Interdisciplinary Research.
The National Center of Competence in Research (NCCR) TransCure, funded by the Swiss National Science Foundation and the University of Bern, was active from 2010 to 2022. It provided unique research and educational framework in the membrane transporter and ion channel field. Thanks to an interdisciplinary approach comprising physiology, structural biology, and chemistry, in parallel to a rich offer in complementary areas such as education and technology transfer, the network achieved outstanding scientific results and contributed to the education of young scientists. In this review, we present the main features and milestones of the NCCR TransCure.


Efficient protein alignment algorithm for protein search.
Proteins show a great variety of 3D conformations, which can be used to infer their evolutionary relationship and to classify them into more general groups; therefore protein structure alignment algorithms are very helpful for protein biologists. However, an accurate alignment algorithm itself may be insufficient for effective discovering of structural relationships among tens of thousands of proteins. Due to the exponentially increasing amount of protein structural data, a fast and accurate structure alignment tool is necessary to access protein classification and protein similarity search; however, the complexity of current alignment algorithms are usually too high to make a fully alignment-based classification and search practical. We have developed an efficient protein pairwise alignment algorithm and applied it to our protein search tool, which aligns a query protein structure in the pairwise manner with all protein structures in the Protein Data Bank (PDB) to output similar protein structures. The algorithm can align hundreds of pairs of protein structures in one second. Given a protein structure, the tool efficiently discovers similar structures from tens of thousands of structures stored in the PDB always in 2 minutes in a single machine and 20 seconds in our cluster of 6 machines. The algorithm has been fully implemented and is accessible online at our webserver, which is supported by a cluster of computers. Our algorithm can work out hundreds of pairs of protein alignments in one second. Therefore, it is very suitable for protein search. Our experimental results show that it is more accurate than other well known protein search systems in finding proteins which are structurally similar at SCOP family and superfamily levels, and its speed is also competitive with those systems. In terms of the pairwise alignment performance, it is as good as some well known alignment algorithms.


Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care.
Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.


Exploring the interactions between Helicobacter pylori (Hp) infection and other risk factors of gastric cancer: A pooled analysis in the Stomach cancer Pooling (StoP) Project.
Helicobacter pylori (Hp) is crucial in gastric carcinogenesis, but infection alone is not a sufficient cause, and the interaction between Hp infection and other risk factors has not been adequately studied. We conducted a pooled analysis of seven case-control studies from the Stomach cancer Pooling (StoP) Project, comprising 1377 cases and 2470 controls, to explore the interaction among Hp infection and tobacco smoking, alcohol drinking, socioeconomic status (SES) and dietary salt intake on the risk of gastric cancer. We estimated summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by multivariate unconditional logistic regression. The analysis showed no consistent interaction between Hp infection and cigarette smoking, while interaction was more than multiplicative for alcohol drinking (OR = 1.38, 95% CI: 1.07-1.77, P-interaction 0.02) and high intake of salt (OR = 2.62, 95% CI: 1.88-3.65, P-interaction = 0.04). The interaction with SES followed the multiplicative model (P = 0.49), resulting in a weakening among infected individuals of the protective effect of high SES among observed Hp-negative individuals. The interactions found were more pronounced in subjects with history of peptic ulcer. The interactions with Hp infection were stronger for cigarette smoking and dietary salt in the case of noncardia cancer, and for alcohol and SES in the case of cardia cancer. No differences were found when stratifying for histologic type. This large-scale study aimed to quantify the interaction between Hp infection and other modifiable risk factors of gastric cancer revealed that the benefit of combined Hp eradication and lifestyle modification on gastric cancer prevention may be larger than commonly appreciated.


The cellular immunotherapy of viral infection.
Viral infections remain a major problem for the patient who has undergone a stem cell transplant and the introduction of increasingly more intensive SCT regimens suggests that this will remain a significant concern for the immediate future. Advances in basic immunology have led to an improved understanding of how immune responses control individual viral infections and this information is now being directly applied to patient care with encouraging results. The application of cellular immunotherapy to the immunocompromised patient is one of the most exciting areas of clinical medicine and offers the prospect of significant clinical impact.


Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration.
Several studies indicate that age-related macular degeneration (AMD) and atherosclerosis may share common pathogenetic pathways. The aim of this study was to determine the role of systemic matrix metalloproteinases (MMPs) in AMD, given that MMPs are implicated in the pathogenesis of atherosclerosis. This study determined the plasma matrix metalloproteinases (MMP-2 and MMP-9) levels in three groups of subjects: group 1 included subjects with age-related maculopathy (ARM), group 2 included subjects with choroidal neovascularization (CNV) owing to AMD and group 3 consisted of age-matched controls. The mean plasma levels of MMP-2 were not significantly different in the three groups. In contrast, the mean plasma MMP-9 levels were significantly higher in ARM and CNV groups compared to that of the control group. However, there was no significant difference in MMP-9 levels between ARM and CNV groups. This is the first study that reveals a link between raised plasma MMP-9 levels with AMD. Further studies are required to identify the factors that contribute to this association.


The concentration of glycine by preparations of the yeast Saccharomyces Carlsbergensis depleted of adenosine triphosphate: Effects of proton gradients and uncoupling agents.
1. At pH 4.5 and 30degreesC, yeast preparations depleted of ATP in the presence of antimycin and deoxyglucose spontaneously lost K+, gaining roughly an equivalent amount of H+. 2. Five proton conductors including azide and 2,4-dinitrophenol accelerated this process, as did [14C]glycine, which was absorbed with two extra equivalents of H+. 3. The rate of glycine uptake at pH 4.5 diminished fourfold when cellular K+ fell by 20%. 4. The distribution of [14C]propionate indicated that the intracellular pH fell from 6.2 to 5.7 when the cellular content of K+ fell by 30%. 5. Glycine uptake from a 5 muM solution was about 400 times faster at pH 4.5 than it was at pH 7.4 with 100mM-KC1 present ostensibly to lower the membrane potential. 6. Yeast preparations containing 2mM-[14C]glycine absorbed a further amount from a 0.1 muM solution at pH 4.5. After about 10 min a net movement of [14C]glycine out of the yeast occurred. The ratio of the cellular [14Ia1glycine concentration to the concentration outside the yeast reached 4 X 10(4) in these assays, whereas at pH 7.4 in the presence of 100mM-KC1 it did not exceed 15 in 3h. Dimitrophenol lowered the accumulation ratio at pH 4.5, apparently by causing proton conduction. 7. The observations are consistent with the notion that glycine uptake is driven by a proton symport mechanism. 8. Possible factors governing the strikingly low rate of glycine efflux as opposed to its optimum rate of influx are discussed.


[Response to the six-minute walk test in children with cardiovascular risk].
Cardiovascular risk (CVR) is defined as the possibility of a subject suffering from car diovascular disease within a certain period. Although the pathology appears in adult life, the physiopathological changes start to develop at an early age. To establish the relationship bet ween cardiorespiratory capacity (CRC)and CVR in children with metabolic syndrome. We analyzed data corresponding to 42 children aged from 5 to 15 years who were seen at the Children's Cardiology Unit of the Carlos Van Buren Hospital between 2015 and 2017. Each parti cipant was categorized according to the Alustiza's CVR score, which defines 3 levels of risk: low (0 to 6 points), medium (7 to 8 points) and high (9 or more points), which representing a greater probability of developing cardiovascular disease, and performed 6MWT. The mean age of the children was 10.9 ± 2.7 years, body mass index (BMI) = 31.0 ± 4.6 kg/m2 (z-score 3.2 ± 0.7), percentage of theoretical distance walked = 75.2 ± 8.9, and percentage of heart rate reserve (HRR) = 31.0 ± 9.4. There was no statistical association between 6MWT and CVR. There is no relationship between the cardiorespiratory capacity and the CVR. The use of the 6MWT is questioned as an ins trument to assess CVR in the population under study.


Pandemic lockdown, healthcare policies and human rights: integrating opposed views on COVID-19 public health mitigation measures.
The issue of the COVID-19 pandemic occupies the agenda of the whole world. The pivot of this pandemic is a crucial element that has become almost as important as the virus itself, namely the lockdown. Although, the rationale for lockdown is well-sustained by strong epidemiological arguments, exploring the 'other' unwanted consequences of the contemporary COVID-19 pandemic is mandatory for coagulating a robust agreed position against the numerous problems generated by the SARS-CoV-2 virus. Starting from the rationale of the lockdown, in this paper we explored and exposed the other consequences of the COVID-19 pandemic measures such as the use or abuse of human rights and freedom restrictions, economic issues, marginalized groups and eclipse of all other diseases. Our scientific attempt is to coagulate a stable position and integrate current opposing views by advancing the idea that rather than applying the uniform lockdown policy, one could recommend instead an improved model targeting more strict and more prolonged lockdowns to vulnerable risk/age groups while enabling less stringent measures for the lower-risk groups, minimizing both economic losses and deaths. Rigorous (and also governed by freedom) debating may be able to synchronize the opposed perspectives between those advocating an extreme lockdown (e.g., most of the epidemiologists and health experts), and those criticizing all restrictive measures (e.g., economists and human rights experts). Confronting the multiple facets of the public health mitigation measures is the only way to avoid contributing to history with yet another failure, as seen in other past epidemics.


The effect of enterocin A/P dipeptide on growth performance, glutathione-peroxidase activity, IgA secretion and jejunal morphology in rabbits after experimental methicillin-resistant Staphylococcus epidermidis P3Tr2a Infection.
The increasing frequency of methicillin-resistant (MR) staphylococci in humans and animals need special attention for their difficult treatment and zoonotic character, therefore novel antimicrobial compounds on a natural base against antibiotic-resistant bacteria are requested. Currently, bacteriocins/enterocins present a new promising way to overcome this problem, both in prevention and treatment. Therefore, the preventive and medicinal effect of dipeptide enterocin EntA/P was evaluated against MR Staphylococcus epidermidis SEP3/Tr2a strain in a rabbit model, testing their influence on growth performance, glutathione-peroxidase (GPx) enzyme activity, phagocytic activity (PA), secretory (s)IgA, and jejunal morphometry (JM). Eighty-eight rabbits (aged 35 days, meat line M91, both sexes) were divided into experimental groups S (SEP3/Tr2a strain; 1.0 × 105 CFU/mL; dose 500µL/animal/day for 7 days, between days 14 and 21 to simulate the pathogen attack), E (EntA/P; 50 µL/animal/day, 25,600 AU/mL in two intervals, for preventive effect between days 0 and 14; for medicinal effect between days 28 and 42), E + S (EntA/P + SEP3/Tr2a; preventive effect; SEP3/Tr2a + EntA/P; medicinal effect) and control group (C; without additives). Higher body weight was recorded in all experimental groups (p < 0.001) compared to control data. The negative influence/attack of the SEP3Tra2 strain on the intestinal immunity and environment was reflected as decreased GPx activity, worse JM parameters and higher sIgA concentration in infected rabbits. These results suggest the promising preventive use of EntA/P to improve the immunity and growth of rabbits, as well as its therapeutic potential and protective role against staphylococcal infections in rabbit breeding.


Maternal Obesity and Neck Circumference.
Obese women are more likely to require general anaesthesia for an obstetric intervention than non-obese. Difficult tracheal intubation and oxygen desaturation is more common in pregnancy. Failed tracheal intubation has been associated with an increase in neck circumference (NC). We studied the relationship between maternal obesity and NC as pregnancy advanced in women attending a standard antenatal clinic. Of the 96 women recruited, 13.5% were obese. The mean NC was 36.8cm (SD 1.9) in the obese women compared with 31.5cm (SD 1.6) in women with a normal BMI (p < 0.001) at 18-22 weeks gestation. In the obese women it increased on average by 1.5cm by 36-40 weeks compared with an increase of 1.6 cm in women with a normal BMI. The antenatal measurement of NC is a simple, inexpensive tool that is potentially useful for screening obese women who may benefit from an antenatal anaesthetic assessment.


Targeting B Cell Signaling in Chronic Lymphocytic Leukemia.
In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development.


Structural analysis of a rabbit immunoglobulin kappa 2 J-C locus reveals multiple deletions.
We previously reported that domestic rabbits harbor at least two DNA sequences that hybridize strongly to immunoglobulin kappa C region probes in Southern blots. One of these was cloned from a domestic b4 rabbit and identified as the gene for the nominal b4 allotype kappa chain which is expressed at high levels. We now have cloned (from a b4 rabbit) the other homologous sequence and find that it encodes a kappa chain nearly identical to the kappa 2 chain of "bas" rabbits, which is not normally expressed at detectable levels in domestic rabbits. Sequence analysis of this kappa 2 chain reveals a J kappa -C kappa locus with no obvious coding sequence defects that could explain its low expression. However, several base changes in a putative enhancer region as well as deletions (totalling about 1.5 kb) in the J-C intron might be related to low expression. The comparison between these two kappa genes raises questions about the selective pressures operating during the evolution of this gene system.


Can the Mediterranean diet lower HbA1c in type 2 diabetes? Results from a randomized cross-over study.
To investigate the impact of a diet modeled on the traditional Cretan Mediterranean diet on metabolic control and vascular risk in type 2 diabetes. Twenty-seven subjects (47-77 yrs) with type 2 diabetes were randomly assigned to consume either the intervention diet ad libitum or their usual diet for 12 weeks and then cross over to the alternate diet. Most of the meals and staple foods for the intervention diet were provided. Lipids, glycemic variables, blood pressure, homocysteine, C-reactive protein, plasma carotenoids and body composition (anthropometry and dual energy X-ray absorptiometry) were assessed at baseline, and at the end of both diet periods. Dietary adherence was monitored using plasma carotenoid and fatty acid (FA) analysis, complemented by diet diaries. Compared with usual diet, on the ad libitum Mediterranean intervention diet glycosylated haemoglobin fell from 7.1% (95% CI: 6.5-7.7) to 6.8% (95% CI: 6.3-7.3) (p=0.012) and diet quality improved significantly [plant:animal (g/day) food ratio increased from 1.3 (95% CI: 1.1-1.5) to 5.4 (95% CI: 4.3-6.6) (p<0.001)], plasma lycopene and lutein/zeaxanthin increased (36% and 25%, respectively), plasma saturated and trans FAs decreased, and monounsaturated FAs increased. A traditional moderate-fat Mediterranean diet improves glycemic control and diet quality in men and women with well-controlled type 2 diabetes, without adverse effects on weight.


The dynamics of the electrotactic reaction of mouse 3T3 fibroblasts.
The molecular mechanisms behind electrotaxis remain largely unknown, with no identified primary direct current electric field (dcEF) sensor. Two leading hypotheses propose mechanisms involving the redistribution of charged components in the cell membrane (driven by electrotaxis of electroosmosis) and the asymmetric activation of ion channels. To investigate these mechanisms, we studied the dynamics of electrotactic behaviour of mouse 3T3 fibroblasts. We observed that 3T3 fibroblasts exhibit cathodal migration within just 1 min when exposed to physiological dcEF. This rapid response suggests the involvement of ion channels in the cell membrane. Our large-scale screening method identified several ion channel genes as potential key players, including the inwardly rectifying potassium channel Kir4.2. Blocking the Kir channel family with Ba2+ or silencing the Kcnj15 gene, encoding Kir4.2, significantly reduced the directional migration of 3T3 cells. Additionally, the levels of the intracellular regulators of Kir channels, spermine (SPM) and spermidine (SPD), had a significant impact on cell directionality. Interestingly, inhibiting Kir4.2 resulted in the temporary cessation of electrotaxis for approximately 1-2 h before its return. This observation suggests a two-phase mechanism for the electrotaxis of mouse 3T3 fibroblasts, where ion channel activation triggers the initial rapid response to dcEF, and the subsequent redistribution of membrane receptors sustains long-term directional movement. In summary, our study unveils the involvement of Kir channels and proposes a biphasic mechanism to explain the electrotactic behaviour of mouse 3T3 fibroblasts, shedding light on the molecular underpinnings of electrotaxis.


Molecular tools for inactivating a yeast enzyme in vivo.
As part of an effort to develop a new means of inducibly inactivating cellular proteins in vivo, three monoclonal antibodies which neutralize yeast alcohol dehydrogenase (ADH) activity were isolated and characterized with respect to criteria important for the inactivation strategy. The significance of these criteria is considered, and a general means of generating appropriate antibodies is suggested. All three antibodies described here were specific for ADH I; they did not recognize the closely related isozyme ADH II in a plate-binding assay and did not immunoprecipitate molecules other than ADH from a Saccharomyces cerevisiae extract. Neutralization occurred in a yeast extract and, for two antibodies, was blocked by high concentrations of the coenzyme NAD+. This finding suggests that the antibodies may block enzyme activity by stabilizing an inactive form of ADH lacking bound NAD+. These results provide a foundation for the use of these antibodies to inactivate ADH in vivo.


The impact of environmental heterogeneity on genetic architecture in a wild population of Soay sheep.
This work demonstrates that environmental conditions experienced by individuals can shape their development and affect the stability of genetic associations. The implication of this observation is that the environmental response may influence the evolution of traits in the wild. Here, we examined how the genetic architecture of a suite of sexually dimorphic traits changed as a function of environmental conditions in an unmanaged population of Soay sheep (Ovis aries) on the island of Hirta, St. Kilda, northwest Scotland. We examined the stability of phenotypic, genetic, and environmental (residual) covariance in males during the first year of life between horn length, body weight, and parasite load in environments of different quality. We then examined the same covariance structures across environments within and between the adult sexes. We found significant genotype-by-environment interactions for lamb male body weight and parasite load, leading to a change in the genetic correlation among environments. Horn length was genetically correlated with body weight in males but not females and the genetic correlation among traits within and between the sexes was dependent upon the environmental conditions experienced during adulthood. Genetic correlations were smaller in more favorable environmental conditions, suggesting that in good environments, loci are expressed that have sex-specific effects. The reduction in genetic correlation between the sexes may allow independent evolutionary trajectories for each sex. This study demonstrates that the genetic architecture of traits is not stable under temporally varying environments and highlights the fact that evolutionary processes may depend largely upon ecological conditions.


Transepiphyseal resection for osteosarcoma in patients with open physes using MRI assessment.
For paediatric and adolescent patients with growth potential, preservation of the physiological joint by transepiphyseal resection (TER) of the femur confers definite advantages over arthroplasty procedures. We hypothesized that the extent of the tumour and changes in its extent after neoadjuvant chemotherapy are essential factors in the selection of this procedure, and can be assessed with MRI. The oncological and functional outcomes of the procedure were reviewed to confirm its safety and efficacy. We retrospectively reviewed 16 patients (seven male and nine female, mean age 12.2 years (7 to 16)) with osteosarcoma of the knee who had been treated by TER. We evaluated the MRI scans before and after neoadjuvant chemotherapy for all patients to assess the extent of the disease and the response to treatment. The mean follow-up period was 64.3 months (25 to 148) after surgery and no patients were lost to follow-up. On MRI evaluation, 13 tumours were near but not in contact with the physes and three tumours were partially in contact with the physes before neoadjuvant chemotherapy. Bone oedema in the epiphysis was observed in eight patients. After neoadjuvant chemotherapy, bone oedema in the epiphysis disappeared in all patients. In total, 11 tumours were not in contact and five tumours were in partial contact with the physes. The postoperative pathological margin was negative in all patients. At the last follow-up, 12 patients were continuously disease-free and three had no evidence of disease. One patient died due to the disease. Functionally, the patients with retained allograft or recycled autograft had a mean knee range of flexion of 126° (90° to 150°). The mean Musculoskeletal Tumor Society functional score was 27.6 (23 to 30). TER is an effective limb-salvage technique for treating malignant metaphyseal bone tumours in paediatric and young osteosarcoma patients with open physes when a good response to chemotherapy and no progression of the tumour to the epiphysis have been confirmed by MRI. Cite this article: Bone Joint J 2020;102-B(6):772-778.


Transesophageal ultrasonography for lung cancer staging: learning curves of pulmonologists.
Accurate mediastinal nodal staging is essential for patients with resectable non-small-cell lung cancer and is achieved by combined endobronchial ultrasound and transesophageal endoscopic ultrasound (EUS). Training requirements for EUS-guided fine-needle aspiration (FNA) for lung cancer staging are unknown. Pulmonologists from Denmark and The Netherlands were enrolled in a dedicated, supervised training program. They performed standardized EUS-FNA procedures for mediastinal nodal analysis and their performances were assessed by EUS experts using a validated EUS assessment tool. Data were collected prospectively and used to plot learning curves and relate these to procedures performed by experienced investigators. Four participants performed 91 EUS-FNA procedures (range, 19-24). The performances of the participants improved significantly and became more consistent, but were still highly variable even in the latter part of the learning curves. Only two of the participants reached the mean score of experienced operators-after 17 and 23 procedures, respectively. Pulmonologists with knowledge of lung cancer staging and experience in bronchoscopy quickly improved their performance of EUS-FNA. However, acquisition of skills varies between individuals, and certification should be based on assessment of performance of multiple cases. Twenty procedures were not enough to secure consistent and competent performance of all trainees.


Effective bond orders from two-step spin-orbit coupling approaches: the I2, At2, IO(+), and AtO(+) case studies.
The nature of chemical bonds in heavy main-group diatomics is discussed from the viewpoint of effective bond orders, which are computed from spin-orbit wave functions resulting from spin-orbit configuration interaction calculations. The reliability of the relativistic correlated wave functions obtained in such two-step spin-orbit coupling frameworks is assessed by benchmark studies of the spectroscopic constants with respect to either experimental data, or state-of-the-art fully relativistic correlated calculations. The I2, At2, IO(+), and AtO(+) species are considered, and differences and similarities between the astatine and iodine elements are highlighted. In particular, we demonstrate that spin-orbit coupling weakens the covalent character of the bond in At2 even more than electron correlation, making the consideration of spin-orbit coupling compulsory for discussing chemical bonding in heavy (6p) main group element systems.


Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi.
A specific prognostication score for hepatitis C virus-positive diffuse large B-cell lymphomas is not available. For this purpose, the Fondazione Italiana Linfomi (FIL, Italian Lymphoma Foundation) carried out a multicenter retrospective study on a large consecutive series of patients with hepatitis C virus-associated diffuse large B-cell lymphoma to evaluate the prognostic impact of clinical and virological features and to develop a specific prognostic score for this subset of patients. All prognostic evaluations were performed on 535 patients treated with an anthracycline-based induction regimen (with rituximab in 255 cases). Severe hepatotoxicity was observed in 14% of patients. The use of rituximab was not associated with increased rate of severe hepatotoxicity. Three-year overall survival and progression-free survival were 71% and 55%, respectively. At multivariate analysis, ECOG performance status of 2 or over, serum albumin below 3.5 g/dL and HCV-RNA viral load over 1000 KIU/mL retained prognostic significance. We combined these 3 factors in a new "HCV Prognostic Score" able to discriminate 3 risk categories with different overall and progression-free survival (low=0; intermediate=1; high-risk ≥2 factors; P<0.001). This score retained prognostic value in the subgroups of patients treated with and without rituximab (P<0.001). The new score performed better than the International Prognostic Index at multivariate analysis and Harrel C-statistic. With the use of three readily available factors (performance status, albumin level and HCV-RNA viral load), the new "HCV Prognostic Score" is able to identify 3 risk categories with different survival, and may be a useful tool to predict the outcome of hepatitis C virus-associated diffuse large B-cell lymphomas.


Hearing loss and acquired immune deficiency syndrome: systematic review.
To investigate the occurrence of hearing loss in individuals with HIV/AIDS and their characterization regarding type and degree. It was conducted a systematic review of the literature found on the electronic databases PubMed, EMBASE, ADOLEC, IBECS, Web of Science, Scopus, Lilacs and SciELO. The search strategy was directed by a specific question: "Is hearing loss part of the framework of HIV/AIDS manifestations?", and the selection criteria of the studies involved coherence with the proposed theme, evidence levels 1, 2 or 3, and language (Portuguese, English and Spanish). We found 698 studies. After an analysis of the title and abstract, 91 were selected for full reading. Out of these, 38 met the proposed criteria and were included on the review. The studies reported presence of conductive, sensorineural, and mixed hearing loss, of variable degrees and audiometric configurations, in addition to tinnitus and vestibular disorders. The etiology can be attributed to opportunistic infections, ototoxic drugs or to the action of virus itself. The auditory evoked potentials have been used as markers of neurological alterations, even in patients with normal hearing. HIV/AIDS patients may present hearing loss. Thus, programs for prevention and treatment of AIDS must involve actions aimed at auditory health.


[Management of Helicobacter pylori infection in primary care in Spain].
The indications on when and how to diagnose and treat ulcerative disease and Helicobacter pylori infection are reasonably clear. The aim of this study was to evaluate the management of H. pylori infection and access to diagnostic tests in primary care. We performed an observational, cross-sectional study. An anonymous questionnaire was sent to Spanish primary care physicians throughout Spain. Compliance with the major consensus conference recommendations on H. pylori treatment was evaluated. The questionnaire was completed by 991 primary care physicians. A total of 87.7% of respondents reported they had indicated eradication therapy at least once during the previous year: 79.9% for duodenal ulcer, 75.3% for gastric ulcer, and 18.3% for gastroesophageal reflux disease. The treatment schedule was correct according to the consensus in 74.7% of the responses. However, 29% prescribed 14-day therapy, which is longer than the recommended duration. Sixty-seven per cent of practitioners maintained continuous or intermittent anti-secretory treatment in asymptomatic ulcerous patients and did not indicate H. pylori eradication therapy. The availability of different tests was as follows: 64.7% of respondents had access to endoscopy, 67.4% to urea breath test, 59.6% to serology, and 11.9% to the H. pylori stool antigen test. There were substantial regional variations in access to diagnostic tests. Management of H. pylori infection is reasonably well adapted to consensus recommendations. Nevertheless, there is marked geographic variation and substantial restrictions in access to diagnostic tests, which hampers application of the recommendations.


The Diagnostic Efficacy of the American College of Radiology (ACR) Thyroid Imaging Report and Data System (TI-RADS) and the American Thyroid Association (ATA) Risk Stratification Systems for Thyroid Nodules.
This study is aimed at evaluating the diagnostic efficacy of ultrasound-based risk stratification for thyroid nodules in the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) and the American Thyroid Association (ATA) risk stratification systems. 286 patients with thyroid cancer were included in the tumor group, with 259 nontumor cases included in the nontumor group. The ACR TI-RADS and ATA risk stratification systems assessed all thyroid nodules for malignant risks. The diagnostic effect of ACR and ATA risk stratification system for thyroid nodules was evaluated by receiver operating characteristic (ROC) analysis using postoperative pathological diagnosis as the gold standard. The distributions and mean scores of ACR and ATA rating risk stratification were significantly different between the tumor and nontumor groups. The lesion diameter > 1 cm subgroup had higher malignant ultrasound feature rates detected and ACR and ATA scores. A significant difference was not found in the ACR and ATA scores between patients with or without Hashimoto's disease. The area under the receiver operating curve (AUC) for the ACR TI-RADS and the ATA systems was 0.891 and 0.896, respectively. The ACR had better specificity (0.90) while the ATA system had higher sensitivity (0.92), with both scenarios having almost the same overall diagnostic accuracy (0.84). Both the ACR TI-RADS and the ATA risk stratification systems provide a clinically feasible thyroid malignant risk classification, with high thyroid nodule malignant risk diagnostic efficacy.


Protective effect of ethanolic extract of Urtica urens L. against the toxicity of imidacloprid on bone remodeling in rats and antioxidant activities.
Imidacloprid (IMI) is very harmful to human health and cause problems. Recently, plants have been considered as potential agents for protection against these disorders. Urtica urens L. (UU) is very useful for relieving rheumatic pains and there is no scientific evidence justifying its use, which lets us think of its direct effect on the bone. This study aimed to investigate the protective effect of UU against toxicity effects of IMI in female rat. Rats were divided into control group, 3 groups treated with IMI at 50, 200 or 300mg/kg/day and 3 groups co-treated with IMI (50, 200 or 300mg/kg/day)+100mg/kg/day of UU. We studied bone remodeling through histological, histomorphometry and biochemical analyses. In IMI- treated groups, we have noted, following histomorphomotric analysis, significant decreases in cortical, trabecular thicknesses and osteoid surfaces. Elsewhere, IMI intoxication significantly decreased serum vitamin D and hydroxyproline levels in the groups treated for 60days. IMI intoxication increased significantly calcium, phosphorus contents, MDA and AOPP levels and the rate of calcification. It decreased significantly GSH, GPx, SOD, CAT, 17b-Estradiol and vitamin E levels, induces a tendency of rarefaction and increases of intrabecular spaces. The co-treatment with UU improved all biochemical parameters (hydroxyproline, MDA, AOPP, GSH, GPx, SOD, CAT, 17b-Estradiol, vitamin D, vitamin E calcium, phosphorus). UU leads to a significant increase in cortical, trabecular thicknesses, osteoid surfaces, a decrease in the intrabecular spaces and the rarefaction of bone. In conclusion, IMI inhibits bone remodeling and enhances bone formation. A significant antioxidant activity was also observed in UU and a total of 6 compounds were identified. Co-administration of UU provided a significant protection which might be due to its antioxidant property.


Response of mitochondrial thioredoxin PsTrxo1, antioxidant enzymes, and respiration to salinity in pea (Pisum sativum L.) leaves.
Mitochondria play an essential role in reactive oxygen species (ROS) signal transduction in plants. Redox regulation is an essential feature of mitochondrial function, with thioredoxin (Trx), involved in disulphide/dithiol interchange, playing a prominent role. To explore the participation of mitochondrial PsTrxo1, Mn-superoxide dismutase (Mn-SOD), peroxiredoxin (PsPrxII F), and alternative oxidase (AOX) under salt stress, their transcriptional and protein levels were analysed in pea plants growing under 150 mM NaCl for a short and a long period. The activities of mitochondrial Mn-SOD and Trx together with the in vivo activities of the alternative pathway (AP) and the cytochrome pathway (CP) were also determined, combined with the characterization of the plant physiological status as well as the mitochondrial oxidative indicators. The analysis of protein and mRNA levels and activities revealed the importance of the post-transcriptional and post-translational regulation of these proteins in the response to salt stress. Increases in AOX protein amount correlated with increases in AP capacity, whereas in vivo AP activity was maintained under salt stress. Similarly, Mn-SOD activity was also maintained. Under all the stress treatments, photosynthesis, stomatal conductance, and CP activity were decreased although the oxidative stress in leaves was only moderate. However, an increase in lipid peroxidation and protein oxidation was found in mitochondria isolated from leaves under the short-term salinity conditions. In addition, an increase in mitochondrial Trx activity was produced in response to the long-term NaCl treatment. The results support a role for PsTrxo1 as a component of the defence system induced by NaCl in pea mitochondria, providing the cell with a mechanism by which it can respond to changing environment protecting mitochondria from oxidative stress together with Mn-SOD, AOX, and PrxII F.


Unravelling the antimicrobial activity of peptide hydrogel systems: current and future perspectives.
The use of hydrogels has garnered significant interest as biomaterial and drug delivery platforms for anti-infective applications. For decades antimicrobial peptides have been heralded as a much needed new class of antimicrobial drugs. Self-assembling peptide hydrogels with inherent antimicrobial ability have recently come to the fore. However, their fundamental antimicrobial properties, selectivity and mechanism of action are relatively undefined. This review attempts to establish a link between antimicrobial efficacy; the self-assembly process; peptide-membrane interactions and mechanical properties by studying several reported peptide systems: β-hairpin/β-loop peptides; multidomain peptides; amphiphilic surfactant-like peptides and ultrashort/low molecular weight peptides. We also explore their role in the formation of amyloid plaques and the potential for an infection etiology in diseases such as Alzheimer's. We look briefly at innovative methods of gel characterization. These may provide useful tools for future studies within this increasingly important field.


Notch2 and Proteomic Signatures in Mouse Neointimal Lesion Formation.
Vascular remodeling is associated with complex molecular changes, including increased Notch2, which promotes quiescence in human smooth muscle cells. We used unbiased protein profiling to understand molecular signatures related to neointimal lesion formation in the presence or absence of Notch2 and to test the hypothesis that loss of Notch2 would increase neointimal lesion formation because of a hyperproliferative injury response. Murine carotid arteries isolated at 6 or 14 days after ligation injury were analyzed by mass spectrometry using a data-independent acquisition strategy in comparison to uninjured or sham injured arteries. We used a tamoxifen-inducible, cell-specific Cre recombinase strain to delete the Notch2 gene in smooth muscle cells. Vessel morphometric analysis and immunohistochemical staining were used to characterize lesion formation, assess vascular smooth muscle cell proliferation, and validate proteomic findings. Loss of Notch2 in smooth muscle cells leads to protein profile changes in the vessel wall during remodeling but does not alter overall lesion morphology or cell proliferation. Loss of smooth muscle Notch2 also decreases the expression of enhancer of rudimentary homolog, plectin, and annexin A2 in vascular remodeling. We identified unique protein signatures that represent temporal changes in the vessel wall during neointimal lesion formation in the presence and absence of Notch2. Overall lesion formation was not affected with loss of smooth muscle Notch2, suggesting compensatory pathways. We also validated the regulation of known injury- or Notch-related targets identified in other vascular contexts, providing additional insight into conserved pathways involved in vascular remodeling.


New Labdanes with Antimicrobial and Acaricidal Activity: Terpenes of Callitris and Widdringtonia (Cupressaceae).
In spite of the evidence for antimicrobial and acaricidal effects in ethnobotanical reports of Callitris and Widdringtonia, the diterpene acids from Widdringtonia have never been described and no comparison to the Australian clade sister genus Callitris has been made. The critically endangered South African Clanwilliam cedar, Widdringtonia wallichii (syn. W. cedarbergensis), of the Cederberg Mountains was once prized for its enduring fragrant timbers and an essential oil that gives an aroma comparable to better known Mediterranean cedars, predominantly comprised by widdrol, cedrol, and thujopsene. In South Africa, two other 'cedars' are known, which are called W. nodiflora and W. schwarzii, but, until now, their chemical similarity to W. wallichii has not been investigated. Much like Widdringtonia, Callitris was once prized for its termite resistant timbers and an 'earthy' essential oil, but predominantly guaiol. The current study demonstrates that the essential oils were similar across all three species of Widdringtonia and two known non-volatile diterpene acids were identified in leaves: the pimaradiene sandaracopimaric acid (1) and the labdane Z-communic acid (2) with a lower yield of the E-isomer (3). Additionally, in the leaves of the three species, the structures of five new antimicrobial labdanes were assigned: 12-hydroxy-8R,17-epoxy-isocommunic acid (4), 8S-formyl-isocommunic acid (5), 8R,17-epoxy-isocommunic acid (6), 8R-17R-epoxy-E-communic acid (7), and 8R-17-epoxy-E-communic acid (8). Australian Callitris columellaris (syn. C. glaucophylla) also produced 1 and its isomer isopimaric acid, pisiferal (9), and pisiferic acid (10) from its leaves. Callitris endlicheri (Parl.) F.M.Bailey yielded isoozic acid (11) as the only major diterpene. Diterpenes 4-6, pisiferic acid (10), spathulenol, and guaiol (12) demonstrated antimicrobial and acaricidal activity.


[Effect of pineal body extract on cytoxan-induced leucopenia in mice].
The effect of pig pineal extract on cytoxan-induced leucopenia in mice was studied. Three preparations of pineal body, Songlesu A, B and C, were used. All of them were effective in leucopenia. They delayed the time of the lowest white count, reduced the extent of white cell reduction and elevated and sustained the white count for several days despite the continuation of cytoxan injection. The effect of Songlesu A was most marked. The differences between the white count of group A (Songlesu A plus cytoxan) and the control (cytoxan plus normal saline) are very significant (P less than 0.01) in a period of 8-15 days after giving the drugs. After discontinuation of medication, the recovery of group A was better than that in the control group also very significantly (P less than 0.01). It is evident that Songlesu A is most worthy of further investigation. However, the effect of Songlesu A was no longer marked from the seventeenth day when the white count started to decline. This is most probably due to the severe bone marrow damage by the large dose of cytoxan accumulated or the protracted daily administration. Moreover, Songlesu A may sensitize the bone marrow to cytoxan toxicity or change the rate of recovery after bone marrow damage.


Occupational risk factors for work disability following carpal tunnel syndrome: a pooled prospective study.
Although recent studies have identified important risk factors associated with incident carpal tunnel syndrome (CTS), risk factors associated with its severity have not been well explored. To examine the associations between personal, workplace psychosocial and biomechanical factors and incident work disability among workers with CTS. Between 2001 and 2010 five research groups conducted coordinated prospective studies of CTS and related work disability among US workers from various industries. Workers with prevalent or incident CTS (N=372) were followed for up to 6.4 years. Incident work disability was measured as: (1) change in work pace or work quality, (2) lost time or (3) job change following the development of CTS. Psychosocial factors were assessed by questionnaire. Biomechanical exposures were assessed by observation and measurements and included force, repetition, duty cycle and posture. HRs were estimated using Cox models. Disability incidence rates per 100 person-years were 33.2 for changes in work pace or quality, 16.3 for lost time and 20.0 for job change. There was a near doubling of risk for job change among those in the upper tertile of the Hand Activity Level Scale (HR 2.17; 95% CI 1.17 to 4.01), total repetition rate (HR 1.75; 95% CI 1.02 to 3.02), % time spent in all hand exertions (HR 2.20; 95% CI 1.21 to 4.01) and a sixfold increase for high job strain. Sensitivity analyses indicated attenuation due to inclusion of the prevalent CTS cases. Personal, biomechanical and psychosocial job factors predicted CTS-related disability. Results suggest that prevention of severe disability requires a reduction of both biomechanical and organisational work stressors.


Signaling between the placenta and the uterus involving the mitogen-regulated protein/proliferins.
The aim of this investigation was to examine signaling between the placenta and uterus during pregnancy. To do this, we determined the tissue messenger RNA and protein levels of members of a glycopeptide hormone family known to stimulate the proliferation of uterine cells and related these levels to the growth of the uterus during pregnancy in the mouse. This hormone family is known as mitogen-regulated protein (MRP); alternatively proliferin (PLF). Three mrp/plf genes, plf1, mrp3 and mrp4, are expressed by the placenta with different developmental profiles. The major increase of about 4-fold in DNA content of the uterus occurs between days 9 and 14 when MRP/PLFs are present in the placenta. By contrast, the gestational changes in estradiol-17beta levels in placental and uterine tissues and in circulation do not correlate with the period of uterine growth. The previously reported mitogenic activity of the MRP/PLFs and their gestational profiles suggest that one or more of these proteins stimulates uterine proliferation during gestation. Evidence is also presented that expression of MRP3 and/or PLF1, but not MRP4, is negatively regulated by feedback from the uterus. Our results are consistent with the hypothesis that MRP/PLFs stimulate uterine proliferation in vivo and that a uterine factor shuts off PLF1 and/or MRP3 synthesis in the latter half of gestation.


Functional analysis of the sialyltransferase complexes in Escherichia coli K1 and K92.
The polysialyltransferase (polyST) structural gene, neuS, for poly alpha 2,8sialic acid (PSA) capsule synthesis in Escherichia coli K1 was previously mapped near the kps region 1 and 2 junction (S. M. Steenbergen and E. R. Vimr, Mol. Microbiol. 4:603-611, 1990). Present Southern and colony blot hybridization results confirmed that neuS was a region 2 locus and indicated apparent homology with neuS from E. coli K92, bacteria that synthesize a sialyl alpha 2,8-2,9-linked polymer. A K1- mutant with an insertion mutation in neuS was complemented in trans by K92 neuS, providing direct evidence that neuS encoded the PSA polymerase. A 2.9-kb E. coli K1 kps subclone was sequenced to better characterize polyST. In addition to neuS, the results identified a new open reading frame, designated neuE, the linker sequence between regions 1 and 2, and the last gene of region 1, kpsS. The kpsS translational reading frame was confirmed by sequencing across the junction of a kpsS'-lacZ+ fusion. PolyST was identified by maxicell analysis of nested deletions and coupled in vitro transcription-translation assays. PolyST's derived primary structure predicted a 47,500-Da basic polypeptide without extensive similarity to other known proteins. PolyST activity was increased 31-fold and was membrane localized when neuS was cloned into an inducible expression vector, suggesting, together with the polyST primary structure, that polyST is a peripheral inner membrane glycosyltransferase. However, polyST could not initiate de novo PSA synthesis, indicating a functional requirement for other kps gene products. The existence of a sialyltransferase distinct from polyST was suggested by identification of a potential polyprenyl-binding motif in a C-terminal membrane-spanning domain of the predicted neuE gene product. Direct evidence for a quantitatively minor sialyltransferase activity, which could function to initiate PSA synthesis, was obtained by phenotypic analysis of mutants with multiple defects in sialic acid synthesis, degradation, and polymerization. The results provide an initial molecular description of K1 and K92 sialyltransferase complexes and suggest a possible common function for accessory kps gene products.


Thrombotic thrombocytopenic purpura presenting as stroke mimics with normal diffusion-weighted MRI.
Thrombotic thrombocytopenic purpura (TTP) is a rare and fatal thrombotic microangiopathy-based hematologic disease. Stroke has been reported as atypical neurological manifestations of TTP in some cases. A 65-year-old male presented with typical acute ischemic stroke symptoms including sudden-onset dysarthria, right-sided facial paralysis and hemiplegia. However, his CT and MRI scans were negative without showing any new ischemic lesions. He was diagnosed with TTP with severe thrombocytopenia, mild anemia, increased LDH, and low ADAMTS-13 activity. The symptoms and positive signs were rapidly resolved after administrating the plasma exchange therapy. Clinicians should consider the possibility of TTP when a patient presents with acute stroke-like symptoms and thrombocytopenia, especially in an emergency room, either with or without new stroke lesions on the brain CT and MRI.


Activation of blood coagulation in autoimmune skin disorders.
The immune system and blood coagulation are simultaneously activated in several inflammatory systemic disorders, such as lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Proinflammatory cytokines, such as IL-6 and TNF-alpha, induce the expression of tissue factor, the main initiator of blood coagulation. Activated proteases of coagulation in turn act on protease-activated receptors, inducing the expression of various proinflammatory cytokines. This cross-talk between inflammation and coagulation amplifies and maintains the activation of both systems. This review focuses on three skin disorders: chronic urticaria (CU), which is considered autoimmune in approximately 50% of cases, bullous pemphigoid (BP), which is the prototype of autoimmune blistering disease, and psoriasis, which is an immune-mediated dermatitis. In CU, the activation of coagulation, which is due to the involvement of eosinophils and tissue factor pathways with the generation of thrombin, has local implications by increasing dermal vascular permeability. Preliminary data indicate that anticoagulant treatment with heparin and warfarin may be effective in reducing the symptoms of this disorder. In BP, the activation of coagulation seems to have both local and systemic implications. Locally, eosinophils and thrombin participate in bulla formation and tissue damage; systemically, the activation of coagulation may explain the increased thrombotic risk observed in these patients. In psoriasis, the activation of coagulation seems to be mainly systemic, potentially contributing to the increased cardiovascular risk associated with this disease.


Cloning of genes participating in aerobic biodegradation of p-cumate from Rhodopseudomonas palustris.
Rhodopseudomonas palustris utilizes p-cumate as a carbon source both under anaerobic light and aerobic dark conditions. A gene cluster was isolated whose sequence showed high homology to genes which have been implicated the degradation of p-cumate in Pseudomonas pitida. Seven structural genes coding for dioxygenase-reductase, dihydroxy-dihydro dehydrogenase, and ring cleavage oxygenases were identified. A putative regulator and its possible recognition site was suggested on the basis of homology data. Mutant cells in which a kanamycin cassette was inserted into the dihydroxy-dihydro dehydrogenase gene could not grow aerobically on p-cumate. The mutation had no effect on growth using the para substituted benzoate derivatives 4-hydroxycinnamate, ferulate, protocatechuate, and 2,3,4-trihydroxybenzoate as sole carbon source. Moreover, mutant cells showed a growth pattern similar to wild type cells grown on these compounds under photoheterotrophic anaerobic conditions. These data suggest that genes of this operon are involved specifically in aerobic dissimilation of p-cumate. Intermediate products of p-cumate degradation could be detected from extracts of Escherichia coli heterologously expressing the first 5 genes responsible for the first two steps of p-cumate degradation in R. palustris. Primer extension analysis revealed the transcription regulation of the gene cluster which could be induced with para methyl-, ethyl- and isopropyl (cumate) benzoates. This is the first report on genes involved in aerobic degradation of these compounds in photosynthetic bacteria.