Comparison of the Effect of PRP, PRF and Induced Bleeding in the Revascularization of Teeth with Necrotic Pulp and Open Apex: A Triple Blind Randomized Clinical Trial.
Treatment of a tooth with necrotic pulp and open apex is a special challenge to the clinicians. Apexification with calcium hydroxide and MTA barrier technique fails to induce continued root maturation which makes the tooth susceptible to root fracture. Hence, an ideal outcome for such a tooth should be regeneration of pulp like tissue into the root canal capable of continuing normal root maturation. This study aims to compare the effect of Platelet Rich Fibrin (PRF), induced bleeding technique and Platelet Rich Plasma (PRP) in the revascularization of tooth with necrotic pulp and open apex. The main objectives of the study were to: (a) Radiographically evaluate the continuation of root development, increase in the dentin wall thickness and narrowing of canal space, apical closure and resolution of the periapical lesion; and to (b) To clinically evaluate the response to pulp sensibility testing and response to percussion and palpation tests. Sixty patients (6 to 28 years) with necrotic immature permanent tooth were randomly categorised into three groups after the root canal disinfection procedure. PRF as scaffolding material (Group A: n=20), revascularization with conventional induced bleeding technique (Group B: n=20), and PRP as the biomaterial (Group C: n=20). The primary outcome variable was measured using Periapical Index (PAI) (for periapical healing), Chen and Chen index (for apical responses), Schei's ruler (for root lengthening and root thickening) and other clinical parameters. The Chi-square test was used to interpret the data among the three groups at the end of 12 months for the variables root lengthening and lateral wall thickness. ANOVA test was performed to compare the mean of the PAI scores of the three groups at preoperative stage and 12 months. If statistically significant, Bonferroni test was done to compare the outcome among the three groups. The significant level was set at p<0.05. Kappa agreement was used to see whether the clinical criteria of success (asymptomatic) were in agreement with radiographic criteria. At the end of 12 months, patients presented with no pain and no signs of reinfection or no radiographic enlargement of the pre-existing apical pathosis in all the three groups. PRP was better than PRF and induced bleeding technique with respect to periapical wound healing when used in the regenerative endodontic procedures. The groups were comparable on grounds of root lengthening and lateral wall thickening. Type 3 apical response was the most common apical response in all the three groups. On analysing the pros and cons of the techniques performed, it is wise to establish induced bleeding technique as the standard endodontic procedure for revascularization of a non vital immature permanent tooth.


Unlike thyrotropin, thyroid-stimulating antibodies do not activate phospholipase C in human thyroid slices.
The effects of thyroid-stimulating antibodies (TSAb) and of thyrotropin (TSH) were compared, on the generation of cyclic AMP and inositol phosphates (InsP), in human thyroid slices incubated in vitro, and on the Rapoport cyclic AMP bioassay. The TSAb positive sera were obtained from 19 patients with Graves' disease. In 14 experiments with the slices system, TSH significantly increased cyclic AMP accumulation (TSH, 0.03-10 mU/ml) as well as the cyclic AMP-independent inositol trisphosphate (InsP3) generation (TSH, 1-10 mU/ml). In the same 14 experiments, TSAb (0.10-28 mg/ml) enhanced cyclic AMP intracellular levels as expected while they did not induce any InsP accumulation. Even when TSAb increased cyclic AMP levels to the same or higher values as those obtained with TSH concentrations allowing InsP3 generation. TSAb were still unable to activate the phosphatidylinositol-Ca2+ cascade. The patterns of the response curves of TSAb and TSH on cyclic AMP accumulation were different, suggesting that different mechanisms may be involved. In addition, unlike TSH, TSAb were not able to stimulate H2O2 generation, which in human tissue mainly depends on the activation of the phosphatidylinositol-Ca2+ cascade. Immunoglobulins from six additional Graves' patients lacking measurable cyclic AMP-stimulating activity in both slices and cells systems did not activate phospholipase C either. In conclusion, our results show that TSAb do not share all the metabolic actions of TSH on human thyroid tissue. The data provide support for the concept that the pathogenesis of Graves' disease can be fully accounted for by the ability of TSAb to stimulate adenylate cyclase. This work also confirms that TSH activates the cyclic AMP and the phosphatidylinositol cascade by independent pathways in the human thyroid.


[The extended amygdala system and self-stimulation of the lateral hypothalamus in rats: modulation with opiates and opioids].
Wistar male rats were implanted with bipolar electrodes in the lateral hypothalamus to study self-stimulation reaction in the Skinner box. Simultaneously, the microcanules were implanted into the central nucleus of the amygdala to inject the drugs studied (1 microl in volume for each injection). The blockade of CRF receptors (astressin 1 microg) or sodium influx ionic currents (xycaine, or lidocain 1 microg) by means of intrastructural administration of drugs into the amygdala descreased self-stimulation reaction of the lateral hypothalamus in rats by 29-55%. The inhibition of D2 and D2 dopamine receptors in the amygdala with SCH23390 (1 microg) or sulpiride (1 microg), respectively. reduced self-stimulation too, but in less degree. On the background of blockade of CRF (astressin) and dopamine (sulpiride) receptors, as well as sodium influx ionic currents (lidocain) in the amygdala neurons, psychomotor stimulant amphetamine (1 mg/kg) and barbiturate sodium ethaminal (5 mg/kg) supported their psychoactivating effect on self-stimulation (+30-37%), but fentanyl (0.1 mg/kg) had got no effect. Fentanyl activated self-stimulation moderately only after blockade D1 dopamine receptors with SCH23390. After blockade of CRF receptors, leu-enkephaline strengthened its depressant effect on self-stimulation reaction (-89%). Therefore, if the modulating influence of the amygdala on the hypothalamus is diminished, the reinforcing effects of opiated (fentanyl) and opioids (leuencephaline) will block, but there will be no effect for psychomotor stimulant amphetamine and barbiturate sodium ethaminal.


Association of household income and adverse outcomes in patients with atrial fibrillation.
Social determinants of health are relevant to cardiovascular outcomes but have had limited examination in atrial fibrillation (AF). The purpose of this study was to examine the association of annual household income and cardiovascular outcomes in individuals with AF. We analysed administrative claims for individuals with AF from 2009 to 2015 captured by a health claims database. We categorised estimates of annual household income as <$40 000; $40-$59 999; $60-$74 999; $75-$99 999; and ≥$100 000. Covariates included demographics, education, cardiovascular disease risk factors, comorbid conditions and anticoagulation. We examined event rates by income category and in multivariable-adjusted models in reference to the highest income category (≥$100 000). Our analysis included 336 736 individuals (age 72.7±11.9 years; 44.5% women; 82.6% white, 8.4% black, 7.0% Hispanic and 2.1% Asian) with AF followed for median (25th and 75th percentile) of 1.5 (95% CI 0.6 to 3.0) years. We observed an inverse association between income and heart failure and myocardial infarction (MI) with evidence of progressive risk across decreased income categories. Individuals with household income <$40 000 had the greatest risk for heart failure (HR 1.17; 95% CI 1.05 to 1.30) and MI (HR 1.18; 95% CI 0.98 to 1.41) compared with those with income ≥$100 000. We identified an association between lower household income and adverse outcomes in a large cohort of individuals with AF. Our findings support consideration of income in the evaluation of cardiovascular risk in individuals with AF.


Molecular Simulations with in-deMon2k QM/MM, a Tutorial-Review.
deMon2k is a readily available program specialized in Density Functional Theory (DFT) simulations within the framework of Auxiliary DFT. This article is intended as a tutorial-review of the capabilities of the program for molecular simulations involving ground and excited electronic states. The program implements an additive QM/MM (quantum mechanics/molecular mechanics) module relying either on non-polarizable or polarizable force fields. QM/MM methodologies available in deMon2k include ground-state geometry optimizations, ground-state Born-Oppenheimer molecular dynamics simulations, Ehrenfest non-adiabatic molecular dynamics simulations, and attosecond electron dynamics. In addition several electric and magnetic properties can be computed with QM/MM. We review the framework implemented in the program, including the most recently implemented options (link atoms, implicit continuum for remote environments, metadynamics, etc.), together with six applicative examples. The applications involve (i) a reactivity study of a cyclic organic molecule in water; (ii) the establishment of free-energy profiles for nucleophilic-substitution reactions by the umbrella sampling method; (iii) the construction of two-dimensional free energy maps by metadynamics simulations; (iv) the simulation of UV-visible absorption spectra of a solvated chromophore molecule; (v) the simulation of a free energy profile for an electron transfer reaction within Marcus theory; and (vi) the simulation of fragmentation of a peptide after collision with a high-energy proton.


New molecular rods--characterization of their interaction with membranes.
Molecular rods are synthetical molecules consisting of a hydrophobic backbone which are functionalized with varying terminal groups. Here, we report on the interaction of a recently described new class of molecular rods with lipid and biological membranes. In order to characterize this interaction, different fluorescently labeled rods were synthesized allowing for the application of fluorescence spectroscopy and microscopy based approaches. Our data show that the rods are incorporated into membranes with a perpendicular orientation to the membrane surface and enrich preferentially in liquid-disordered lipid domains. These characteristics underline that rods can be applied as stable membrane-associated anchors for functionalizing membrane surfaces.


Ulcer disease prophylaxis in koi carp by bath immersion with chicken egg yolk containing anti-Aeromonas salmonicida IgY.
Ulcer disease, caused by atypical Aeromonas salmonicida, is a serious concern in ornamental koi carp, because it induces skin ulceration, disfiguring ornamental fish and causing economic loses. The present study aimed to establish a novel prophylaxis with chicken egg yolk immunoglobulin, IgY, against ulcer disease and to assess its feasibility in the ornamental fish industry. Addition of egg yolk powder containing anti-A. salmonicida IgY to rearing water provided significant protection against an A. salmonicida bath infection, whereas administration of non-specific IgY did not. Consecutive immersion of fish into rearing water containing specific IgY completely prevented ulcer disease resulting from cohabitation infection, indicating that this prophylaxis could prevent infection from such type of contact. Thus, passive immunization induced by immersing fish into aquarium water containing specific IgY is a prospective prophylaxis against diseases caused by pathogens that invade the skin and gills.


Clinical outcomes in patients with the concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention: an analysis from the Guthrie Health Off-Label Stent (GHOST) investigators.
The concomitant use of proton pump inhibitors (PPIs) with clopidogrel is suspected to be associated with an adverse impact on clinical outcomes in patients with coronary artery disease. We sought to evaluate whether the use of PPIs with clopidogrel was associated with worse clinical outcomes after percutaneous coronary intervention (PCI) compared with the use of clopidogrel alone. We studied 2651 consecutive patients discharged alive after coronary stenting for stable or unstable coronary artery disease between 2001 and 2007. All patients received aspirin indefinitely and a thienopyridine for 1 to 12 months. Patients were categorized into 2 groups: those taking a PPI [PPI (+), n=751] and those not taking a PPI [PPI (-), n=1900] at discharge. The primary end points were the 6-month incidence of major adverse cardiovascular events (MACE) (composite of death, myocardial infarction, target vessel revascularization, and stent thrombosis) and net adverse clinical events (NACE) (composite of MACE and thrombolysis in myocardial infarction major or minor bleeding), which were evaluated using propensity-adjusted Cox regression analysis. In addition, propensity-matched analysis was performed in 685 pairs of patients. The PPI (+) group was older and had more comorbid conditions than the PPI (-) group. In propensity-adjusted as well as propensity-matched analyses, the use of PPIs was not associated with an increased risk of MACE or NACE. The use of PPIs with dual antiplatelet therapy was not associated with any adverse influence on MACE or NACE after PCI.


Complex functions of Mef2 splice variants in the differentiation of endoderm and of a neuronal cell type in a sea anemone.
In triploblastic animals, mesoderm gives rise to many tissues and organs, including muscle. By contrast, the representatives of the diploblastic phylum Cnidaria (corals, sea anemones, jellyfish and hydroids) lack mesoderm but possess muscle. In vertebrates and insects, the transcription factor Mef2 plays a pivotal role in muscle differentiation; however, it is also an important regulator of neuron differentiation and survival. In the sea anemone Nematostella vectensis, an organism that lacks mesoderm but has muscles and neurons, Mef2 (Nvmef2) has been reported in single ectodermal cells of likely neural origin. To our surprise, we found that Nvmef2 is alternatively spliced, forming differentially expressed variants. Using morpholino-mediated knockdown and mRNA injection, we demonstrate that specific splice variants of Nvmef2 are required for the proliferation and differentiation of endodermal cells and for the development of ectodermal nematocytes, a neuronal cell type. Moreover, we identified a small conserved motif in the transactivation domain that is crucially involved in the endodermal function of Nvmef2. The identification of a crucial and conserved motif in the transactivation domain predicts a similarly important role in vertebrate Mef2 function. This is the first functional study of a determinant of several mesodermal derivatives in a diploblastic animal. Our data suggest that the involvement of alternative splice variants of Mef2 in endomesoderm and neuron differentiation predates the cnidarian-bilaterian split.


Preoperative factors predicting survival after secondary cytoreduction for recurrent ovarian cancer.
We evaluated preoperative data that may predict benefit from secondary cytoreductive surgery (CRS) to assist in selecting therapy for patients with platinum-sensitive recurrent epithelial ovarian cancer. Inclusion criteria included recurrent epithelial or primary peritoneal carcinoma with an initial disease-free interval more than 6 months after chemotherapy, evidence of disease on imaging studies and indication for surgery being to debulk residual disease. Preoperative CA125 values, computed tomographic findings, and time to progression were evaluated as predictors of survival in addition to postoperative information and perioperative morbidity. Sixty-two patients met the inclusion criteria. In the 35.5% of patients debulked to no visible disease, median survival was significantly longer than in those with less than 1 cm of visible residual disease (5.95 vs 2.73 years, P=0.004), but debulking to less than 1 cm visible disease was not better than those with less than 1 cm residual disease (2.02 years). Mean preoperative CA125 levels were significantly lower in the patients who could be debulked to no visible residual disease compared to less than 1 cm or more than 1 cm residual disease (69.1 vs 290.7 vs 1978.4, P=0.001). Generation of a receiver operating characteristic curve determined that a CA125 cutoff of 250 U/mL best predicted successful cytoreduction to no visible disease. Only patients cytoreduced to no visible disease achieved a survival advantage, and the only preoperative factor that could predict surgical success regarding prolonging survival was a CA125 less than 250 U/mL. These data can guide physicians and patients in deciding whether or not to undergo secondary cytoreduction for first recurrence of ovarian cancer.


Uptake and transport of roxarsone and its metabolites in water spinach as affected by phosphate supply.
Roxarsone (ROX) is widely used as a feed additive in intensive animal production. While an animal is fed with ROX, the As compounds in the manure primarily occur as ROX and its metabolites, including arsenate (As[V]), arsenite (As[III]), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA). Animal manure is commonly land applied with phosphorous fertilizers in China. A pot experiment was conducted to investigate the phytoavailability of ROX, As(V), As(III), MMA, and DMA in water spinach (Ipomoea aquatica), with the soil amended with 0, 0.25, 0.50, 1.0, and 2.0 g PO(4)/kg, respectively, plus 2% (w/w manure/soil) chicken manure (CM) bearing ROX and its metabolites. The results indicate that this species of water spinach cannot accumulate ROX and MMA at detectable levels, but As(V), As(III), and DMA were present in all plant samples. Increased phosphorous decreased the shoot As(V) and As(III) in water spinach but did not affect the root As(V). The shoot DMA and root As(III) and DMA were decreased/increased and then increased/decreased by elevated phosphorous. The total phosphorous content (P) in plant tissue did not correlate with the total As or the three As species in tissues. Arsenate, As(III), and DMA were more easily accumulated in the roots, and phosphate considerably inhibited their upward transport. Dimethylarsinic acid had higher transport efficiency than As(V) and As(III), but As(III) was dominant in tissues. Conclusively, phosphate had multiple effects on the accumulation and transport of ROX metabolites, which depended on their levels. However, proper utilization of phosphate fertilizer can decrease the accumulation of ROX metabolites in water spinach when treated with CM containing ROX and its metabolites.


Migraine-Like Positive Visual Phenomena Related to Focal Cortical Lesions with Undetectable Visual Field Defects.
Migraines are commonly associated with a visual aura that has a characteristic clinical presentation. Cortical lesions within or in close proximity to the retrochiasmal visual pathways may also present in a manner that mimics migrainous visual phenomena and, in some cases, may be too small to manifest with a visual field defect on formal testing. We present 4 patients (3 females and 1 male) with an average age of 48.5 (range 28-67) years who had migraine-like visual disturbances related to a right temporal meningioma, occipital cavernoma, occipital lobe infarction, and demyelination in the optic radiations, which was the presenting sign of multiple sclerosis. No patient underwent neurosurgical intervention, and 1 patient (occipital lobe infarct) had complete resolution of the symptom after initial presentation. All patients had normal visual fields at follow-up and no thinning evident on optical coherence tomography. Our cases emphasize the importance of a history in assessing patients with transient positive visual phenomena and identify pathology that may present without visual field defects. Clinical features that should raise a doubt about a diagnosis of migraine visual aura include the absence of headache, brief visual disturbance lasting <5 min or those lasting >60 min, and age >40, especially with no past medical history of migraine.


Computational evaluation of psoas muscle influence on walking function following internal hemipelvectomy with reconstruction.
An emerging option for internal hemipelvectomy surgery is custom prosthesis reconstruction. This option typically recapitulates the resected pelvic bony anatomy with the goal of maximizing post-surgery walking function while minimizing recovery time. However, the current custom prosthesis design process does not account for the patient's post-surgery prosthesis and bone loading patterns, nor can it predict how different surgical or rehabilitation decisions (e.g., retention or removal of the psoas muscle, strengthening the psoas) will affect prosthesis durability and post-surgery walking function. These factors may contribute to the high observed failure rate for custom pelvic prostheses, discouraging orthopedic oncologists from pursuing this valuable treatment option. One possibility for addressing this problem is to simulate the complex interaction between surgical and rehabilitation decisions, post-surgery walking function, and custom pelvic prosthesis design using patient-specific neuromusculoskeletal models. As a first step toward developing this capability, this study used a personalized neuromusculoskeletal model and direct collocation optimal control to predict the impact of ipsilateral psoas muscle strength on walking function following internal hemipelvectomy with custom prosthesis reconstruction. The influence of the psoas muscle was targeted since retention of this important muscle can be surgically demanding for certain tumors, requiring additional time in the operating room. The post-surgery walking predictions emulated the most common surgical scenario encountered at MD Anderson Cancer Center in Houston. Simulated post-surgery psoas strengths included 0% (removed), 50% (weakened), 100% (maintained), and 150% (strengthened) of the pre-surgery value. However, only the 100% and 150% cases successfully converged to a complete gait cycle. When post-surgery psoas strength was maintained, clinical gait features were predicted, including increased stance width, decreased stride length, and increased lumbar bending towards the operated side. Furthermore, when post-surgery psoas strength was increased, stance width and stride length returned to pre-surgery values. These results suggest that retention and strengthening of the psoas muscle on the operated side may be important for maximizing post-surgery walking function. If future studies can validate this computational approach using post-surgery experimental walking data, the approach may eventually influence surgical, rehabilitation, and custom prosthesis design decisions to meet the unique clinical needs of pelvic sarcoma patients.


Ultrastructural changes detected using swept-source optical coherence tomography in severe vitreopapillary traction: a case report.
Vitreopapillary traction is an uncommon condition characterized by strong adhesion and the traction of the posterior hyaloid onto the optic disc and peripapillary retina, leading to optic disc elevation and visual loss. An 85-year-old man presented with a 6-month history of slow, progressive visual loss in the left eye along with optic disc edema. Swept-source optical coherence tomography B-scans revealed circumpapillary anterior-posterior persistent traction of dense vitreous strands onto the optic disc. Visual field examination demonstrated mild, generalized, diffuse sensitivity loss and blind-spot enlargement. A 25-gauge posterior vitrectomy was performed with posterior hyaloid separation from the optic disc, resulting in significant anatomical and visual improvement. In conclusion, swept-source optical coherence tomography aids in understanding the mechanism underlying visual loss in vitreopapillary traction. Moreover, posterior vitrectomy can effectively promote anatomical and visual improvements in these cases.


[Hysteroscopic diagnostic accuracy in post-menopausal bleeding].
To evaluate the diagnostic accuracy of hysteroscopy at our unit for postmenopausal bleeding, specially concerning proliferative lesions. We analyzed the results of 335 hysteroscopies that were done during the last 8 years in our hysteroscopic unit and we compared the hysteroscopic diagnosis with the biopsy result done during the procedure. Data were group according to pathologic findings in three groups normal, proliferative lesions and benign lesions. Data were analyzed by direct comparison. Sensitivity and specificity were calculated, Kappa index was used to access the inter-rater reliability, and likelihood ratio and the post test probability were used to analyze the true value of hysteroscopy. Women were aged between 36 and 88 years, with an average of 61,5. Histological diagnosis was atrophy in 42,1% patients, polyps in 43,3%, sub-mucous fibromioma in 5%, hyperplasic lesions in 9,6%, half of them being carcinomas. Overall Kappa index for the 3 groups was 0,831 which is in line with excellent agreement. Concerning proliferative lesions (hyperplasia + carcinoma vs carcinoma alone) and comparing to histology, sensitivity was 78,1% vs 81,3%; specificity 95,7% vs 98,7%. The positive likelihood ratio was 18,2 vs 64,8 and the negative likelihood ratio was 0,23 vs 0,19. The probability post positive test was 66% vs 76% and the probability post negative test was 2,4% vs 0,95%. No cases of carcinoma were identified among the 129 women diagnosed as having atrophy. However 3,9% of all the lesions regarded as being polyps at the hysteroscopy proved to be proliferative lesions at hysteroscopy. Hysteroscopy at our unit is a highly accurate procedure concerning post menopausal endometrial bleeding, with its results being in line with the literature. Diagnosing atrophy or excluding a proliferative lesion by the observer was highly predictive of a negative carcinoma in the histology. Using this argument whenever a proliferative lesion was excluded, only 1 in 302 hysteroscopies hid a carcinoma. Polyps should be regarded as possible proliferative lesions. Despite this result we believe a biopsy should always be undertaken no matter the observer's diagnosis.


Assessing energy, environmental, and economic tradeoffs in intermodal freight transportation.
This paper presents an energy and environmental network analysis model to explore tradeoffs associated with freight transport. The geospatial model uses an intermodal network built by the authors to connect various modes (rail, road, water) via intermodal terminals. Routes along the network are characterized not only by temporal and distance attributes, but also by cost, energy, and emissions attributes (including emissions of carbon dioxide, particulate matter, sulfur oxides, volatile organic compounds, and oxides of nitrogen). Decision-makers can use the model to explore tradeoffs among alternative route selection across different modal combinations, and to identify optimal routes for objectives that feature energy and environmental parameters (e.g., minimize carbon dioxide emissions). The model is demonstrated with three case studies of freight transport along the U.S. eastern seaboard.


Berberine enhances the antibacterial activity of selected antibiotics against coagulase-negative Staphylococcus strains in vitro.
Synergistic interactions between commonly used antibiotics and natural bioactive compounds may exhibit therapeutic benefits in a clinical setting. Berberine, an isoquinoline-type alkaloid isolated from many kinds of medicinal plants, has proven efficacy against a broad spectrum of microorganisms. The aim of the presented work was to assess the antibacterial activity of berberine chloride in light of the effect exerted by common antibiotics on fourteen reference strains of Staphylococccus spp., and to evaluate the magnitude of interactions of berberine with these antistaphylococcal antibiotics. In our study minimum inhibitory concentrations (MIC) of berberine chloride against CoNS ranged from 16 to 512 µg/mL. The most noticeable effects were observed for S. haemolyticus ATCC 29970, S. epidermidis ATCC 12228, S. capitis subsp. capitis ATCC 35661, S. galinarium ATCC 700401, S. hominis subsp. hominis ATCC 27844, S. intermedius ATCC 29663 and S. lugdunensis ATCC 49576. The most significant synergistic effect was noticed for berberine in combination with linezolid, cefoxitin and erythromycin. The synergy between berberine and antibiotics demonstrates the potential application of compound combinations as an efficient, novel therapeutic tool for antibiotic-resistant bacterial infections.


Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation.
Tumor necrosis factor alpha (TNFalpha) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNFalpha-inducible reactive oxygen species (ROS) in IL-8 expression by "monocyte-like" U937 histiocytic lymphoma cells. TNFalpha is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFalpha requires the presence of an inducible nuclear factor-kappaB (NF-kappaB) (Rel A) binding site in the IL-8 promoter. TNFalpha treatment induces a rapid translocation of the 65 kD transcriptional activator NF-kappaB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNFalpha with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-kappaB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-kappaB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFalpha induces a delayed ROS-dependent signalling pathway that is required for NF-kappaB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFalpha signalling.


The effect of immunity to core lipopolysaccharides (LPS) on the production of thromboxane and prostacyclin by equine peritoneal macrophages.
An experiment was designed to determine whether a change in the ability of macrophages to respond to lipopolysaccharides (LPS) of gram-negative bacteria was involved in the development of cross-reactive immunity to endotoxemia. The endotoxin-induced production of thromboxane A2(TxA2) and prostacyclin (PGI2) by peritoneal macrophages from horses which were hyperimmunized against the common core region of LPS were compared to those in unimmunized horses. Bacterins used for induction of core LPS immunity were prepared from the J-5 mutant of Escherichia coli 0111:B4, and the R 595 mutant of Salmonella minnesota. Serum antibody titers to core LPS were determined by an indirect enzyme-linked immunosorbent assay. Immunized horses had a marked increase in titer to core LPS (p less than 0.05), while there was no change in titer in unimmunized control horses. The only significant difference in the in vitro LPS-induced production of TxA2 and PGI2 by peritoneal macrophages between immunized and control horses was a greater production of TxA2 by macrophages from immunized horses in response to 10 ng/ml LPS (p less than 0.05). Results of this experiment do not support the concept that cross-reactive immunity to LPS is attended by reduced production of TxA2 and PGI2 by equine peritoneal macrophages.


Candida albicans adherence to a human oesophageal cell line.
The oesophageal epithelium appears to be one of the primary cell targets of Candida albicans in AIDS patients. To study this interaction, we have established an in vitro adherence assay using a human epithelial oesophageal cell line (HET1-A). When yeast cells were grown in 500 mM D-galactose, adherence increased significantly over cultures prepared in 500 mM D-glucose. In addition to HET1-A cells, adherence of the organism grown in D-galactose to human buccal epithelial cells and a murine alveolar macrophage cell line was also higher. Adherence of yeast cells to HET1-A cells was partially inhibited in the presence of D-glucosamine or N-acetyl-D-glucosamine, but not with D-mannose, D-glucose, L-fucose or D-galactose. Attachment to HET1-A cells was studied using scanning and transmission electron microscopy. Partial phagocytosis of adhering yeast cells was observed occasionally within the first 90 min following infection, as evidenced by the formation of HET1-A pseudopodia in instances of close contact with yeast cells. The influence of D-galactose on cell surface proteins was studied by analysing beta-mercaptoethanol-extracted proteins from yeast cells grown in either 500 mM D-galactose or D-glucose. From D-galactose-grown cells only, a glycoprotein of approximately 190 kDa was observed in Aurodye-stained SDS-PAGE gels and in Western blots using an immunoglobulin fraction (IgG) prepared from sera of rabbits infected with the organism. These studies demonstrate that C. albicans adheres to human oesophageal cells and may utilize cell surface proteins whose synthesis is nutritionally regulated.


When identities collide: Conflicts in allegiances among LGB people of color.
Little research has examined the management of multiple minority identities among lesbian, gay, and bisexual (LGB) people of color, despite a growing theoretical literature on such identity intersections. The present study focused on the intersectional construct of conflicts in allegiances (CIA), defined as perceived incompatibility between one's racial/ethnic and sexual orientation identities. CIA was investigated in relation to experiences of parental heterosexism, racism in LGB communities, outness, and racial/ethnic and sexual orientation group identity. Participants were 124 LGB people of color (main sample) and 124 LGB White people (comparison sample) who completed self-report measures of the main variables as part of a larger survey of same-sex couples. CIA was positively correlated with experiences of racism within LGB communities and perceived heterosexism in one's mother (but not one's father), and negatively correlated with outness to family (but not outness to others in one's everyday life). An interaction was found between racial/ethnic and LGB group identity with respect to behavioral engagement: CIA levels were highest among participants with high racial/ethnic behavioral engagement and low sexual orientation behavioral engagement. Results highlight the role of minority and family contexts in CIA among LGB people of color, and, more broadly, the potential value of studying intersectional variables using quantitative methods. Longitudinal and experimental studies are needed to address questions about direction of influence raised by findings.


Limited Link of Common Blood Parameters with Tinnitus.
Background: Tinnitus severity is generally assessed by psychometric and audiological instruments. However, no objective measure exists to evaluate the subjective discomfort and suffering caused by this hearing phenomenon. The objective of this work was to determine the possible blood parameters for diagnostics and therapy. Methods: We measured tinnitus distress by using the Tinnitus Questionnaire (TQ) and collected tinnitus-related audiological measures, namely the hearing threshold (HT), tinnitus loudness (TL), and sensation level (SL, i.e., the tinnitus loudness/hearing threshold at a tinnitus frequency). Blood samples were taken from 200 outpatients of the Tinnitus Centre of the Charité, and 46 routine blood count parameters were examined. The possible interactions were determined by (robust) linear models. Results: Tinnitus distress and audiological measurements were largely uncorrelated but could partly be predicted by selected blood parameters. First, the erythrocyte counts predicted tinnitus distress to a small extent. Second, the levels of vitamin D3 explained about 6% of tinnitus loudness and, age-dependently, the hearing threshold variability. Last, the levels of uric acid explained about 5% of the sensation level variability. Conclusions: Tinnitus is a multidimensional phenomenon. The marginal influences of blood markers suggest the possible roles of inflammation and oxidative stress produced by psychological or somatic burdens. Clinically, a vitamin D substitution (in older patients) might have a hearing-protective effect.


The dynamics of plate tectonics and mantle flow: from local to global scales.
Plate tectonics is regulated by driving and resisting forces concentrated at plate boundaries, but observationally constrained high-resolution models of global mantle flow remain a computational challenge. We capitalized on advances in adaptive mesh refinement algorithms on parallel computers to simulate global mantle flow by incorporating plate motions, with individual plate margins resolved down to a scale of 1 kilometer. Back-arc extension and slab rollback are emergent consequences of slab descent in the upper mantle. Cold thermal anomalies within the lower mantle couple into oceanic plates through narrow high-viscosity slabs, altering the velocity of oceanic plates. Viscous dissipation within the bending lithosphere at trenches amounts to approximately 5 to 20% of the total dissipation through the entire lithosphere and mantle.


Effect of microgrooved surface topography on osteoblast maturation and protein adsorption.
Microgrooved surfaces have been used extensively to influence cell contact guidance. Guiding cell growth, extracellular matrix deposition, and mineralization is important for bone implant longevity. In this study, we investigated the osteoblast response to microgrooved metallic surfaces in serum-supplemented medium. Groove spacing was comparable with the spread osteoblast size. Focal adhesions were observed to confine to the intervening ridge/groove boundaries. Osteoblasts bridged over the grooves and were unable to conform to the concave shape of the underlying grooves. Microgrooved surfaces induced higher osteoblast proliferation and metabolic activity after 14 days in osteogenic medium compared with as-received surfaces, resulting in higher mineralization and alignment of cell-secreted collagen after 28 days. To establish whether preferential cell attachment at the ridge/groove boundaries was influenced by the adhesion proteins contained in the serum-supplemented media, fluorescently labeled fibronectin was adsorbed onto the microgrooved substrates at low concentrations, mimicking the concentrations found in blood serum. Fibronectin was found to selectively adsorb onto the ridge/groove boundaries, the osteoblast focal adhesion sites, suggesting that protein adsorption may have influenced the cell attachment pattern.


Two-step magnetic bead-based (2MBB) techniques for immunocapture of extracellular vesicles and quantification of microRNAs for cardiovascular diseases: A pilot study.
Extracellular vesicles (EVs) have attracted increasing attention because of their potential roles in various biological processes and medical applications. However, isolation of EVs is technically challenging mainly due to their small and heterogeneous size and contaminants that are often co-isolated. We have thus designed a two-step magnetic bead-based (2MBB) method for isolation a subset of EVs as well as their microRNAs from samples of a limited amount. The process involves utilizing magnetic beads coated with capture molecules that recognize EV surface markers, such as CD63. Captured EVs could be eluted from beads or lyzed directly for subsequent analysis. In this study, we used a second set of magnetic beads coated with complementary oligonucleotides to isolate EV-associated microRNAs (EV-miRNAs). The efficiencies of 2MBB processes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) with spiked-in exogenous cel-miR-238 molecules. Experimental results demonstrated the high efficiency in EV enrichment (74 ± 7%, n = 4) and miRNA extraction (91 ± 4%, n = 4). Transmission electron micrographs (TEM) and nanoparticle tracking analysis (NTA) show that captured EVs enriched by 2MBB method could be released and achieved a higher purity than the differential ultracentrifugation (DUC) method (p < 0.001, n = 3). As a pilot study, EV-miR126-3p and total circulating cell-free miR126-3p (cf-miR126-3p) in eight clinical plasma samples were measured and compared with the level of protein markers. Compared to cf-miR126-3p, a significant increase in correlations between EV-miR126-3p and cardiac troponin I (cTnI) and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP) was detected. Furthermore, EV-miR126-3p levels in plasma samples from healthy volunteers (n = 18) and high-risk cardiovascular disease (CVD) patients (n = 10) were significantly different (p = 0.006), suggesting EV-miR126 may be a potential biomarker for cardiovascular diseases. 2MBB technique is easy, versatile, and provides an efficient means for enriching EVs and EV-associated nucleic acid molecules.


Localization of fast MEG waves in patients with brain tumors and epilepsy.
It was investigated if single dipole analysis of spontaneous fast waves (>8 Hz) can be used to determine the location of the epileptic focus. Automatic dipole analysis was applied to MEG data of 25 patients with intracranial tumors and epilepsy. The frequency range of 8-50 Hz was divided into standard EEG bands. MEG results were overlaid on the MRI scans of the patients. Dipoles describing fast wave fields were located in the parietal/occipital cortex, and not at tumor border zones. In the cases that the dipoles were lateralized there was no clear preference to be located ipsi or contralateral to the tumor. However the generators of epileptic activity in these patients are thought to be located in the border areas of the tumors. Therefore it seems unlikely that the dipole locations describing fast waves are related to the epileptic zones in patients with brain tumors and epilepsy. A remarkable finding is that lateralized dipoles tend to be located in the right hemisphere and not in the left hemisphere. This appears to reflect an asymmetry of possibly normal background activity.


Regional distribution of the anticonvulsant and behavioural effects of bicuculline injected into the pontine reticular formation of rats.
Previous experimental work has established that activation of sites in the dorsal midbrain can suppress tonic hindlimb extension in the electroshock model of epilepsy. The most sensitive region for this effect is centred on the intercollicular area and is referred to as the dorsal midbrain anticonvulsant zone (DMAZ). Subsequent experiments have shown that the ipsilateral descending projection from this region to the ventrolateral pons is critically involved in mediating its tonic seizure-suppressing properties. The purpose of the present investigation was to test whether direct anticonvulsant effects in the electroshock model could be obtained from selective manipulation of DMAZ target regions in the ventrolateral pons. Animals were prepared with chronically implanted guide cannulae through which microinjections could be made directly into the lateral pontine reticular formation. Animals received injections of saline or bicuculline (25-100 pmol) administered either bilaterally or unilaterally. The effects of these injections on the animals' behaviour were determined in an open arena, after which maximal electroshock (1 s, 40 mA, 50 Hz AC) was administered via ear-clip electrodes and the duration of tonic hindlimb extension was recorded. Bilateral injections of bicuculline (100 pmol) suppressed tonic seizures at a significantly higher proportion of sites centred on DMAZ target regions of the ventrolateral pons than surrounding areas. For injections centred on this region the suppressive effects of bicuculline were dose-related in the range 25-100 pmol. Unilateral injections of bicuculline into the ventrolateral pons also effectively suppressed tonic seizures in the electroshock model. Within the ventral pons there was a significant association between the behavioural and anticonvulsant effects of bicuculline; injections suppressing tonic seizures were associated with the induction of fast continuous locomotor activity. These data confirm that the DMAZ recipient region of the ventrolateral pontine reticular formation is part of a circuit which can suppress the manifestation of tonic hindlimb extension in the electroshock model. Whether this property is related to the participation of this region in normal locomotion and posture remains to be determined.


Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies.
Tauopathies are classified according to whether tau deposits predominantly contain tau isoforms with three or four repeats of the microtubule-binding domain. Those in which four-repeat (4R) tau predominates are known as 4R-tauopathies, and include progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathies and conditions associated with specific MAPT mutations. In these diseases, 4R-tau deposits are found in various cell types and anatomical regions of the brain and the conditions share pathological, pathophysiological and clinical characteristics. Despite being considered 'prototype' tauopathies and, therefore, ideal for studying neuroprotective agents, 4R-tauopathies are still severe and untreatable diseases for which no validated biomarkers exist. However, advances in research have addressed the issues of phenotypic overlap, early clinical diagnosis, pathophysiology and identification of biomarkers, setting a road map towards development of treatments. New clinical criteria have been developed and large cohorts with early disease are being followed up in prospective studies. New clinical trial readouts are emerging and biomarker research is focused on molecular pathways that have been identified. Lessons learned from failed trials of neuroprotective drugs are being used to design new trials. In this Review, we present an overview of the latest research in 4R-tauopathies, with a focus on progressive supranuclear palsy, and discuss how current evidence dictates ongoing and future research goals.


Employing Nanostructured Scaffolds to Investigate the Mechanical Properties of Adult Mammalian Retinae Under Tension.
Numerous eye diseases are linked to biomechanical dysfunction of the retina. However, the underlying forces are almost impossible to quantify experimentally. Here, we show how biomechanical properties of adult neuronal tissues such as porcine retinae can be investigated under tension in a home-built tissue stretcher composed of nanostructured TiO2 scaffolds coupled to a self-designed force sensor. The employed TiO2 nanotube scaffolds allow for organotypic long-term preservation of adult tissues ex vivo and support strong tissue adhesion without the application of glues, a prerequisite for tissue investigations under tension. In combination with finite element calculations we found that the deformation behavior is highly dependent on the displacement rate which results in Young's moduli of (760-1270) Pa. Image analysis revealed that the elastic regime is characterized by a reversible shear deformation of retinal layers. For larger deformations, tissue destruction and sliding of retinal layers occurred with an equilibration between slip and stick at the interface of ruptured layers, resulting in a constant force during stretching. Since our study demonstrates how porcine eyes collected from slaughterhouses can be employed for ex vivo experiments, our study also offers new perspectives to investigate tissue biomechanics without excessive animal experiments.


Neighborhood environment, social cohesion, and epigenetic aging.
Living in adverse neighborhood environments has been linked to risk of aging-related diseases and mortality; however, the biological mechanisms explaining this observation remain poorly understood. DNA methylation (DNAm), a proposed mechanism and biomarker of biological aging responsive to environmental stressors, offers promising insight into potential molecular pathways. We examined associations between three neighborhood social environment measures (poverty, quality, and social cohesion) and three epigenetic clocks (Horvath, Hannum, and PhenoAge) using data from the Detroit Neighborhood Health Study (n=158). Using linear regression models, we evaluated associations in the total sample and stratified by sex and social cohesion. Neighborhood quality was associated with accelerated DNAm aging for Horvath age acceleration (β = 1.8; 95% CI: 0.4, 3.1), Hannum age acceleration (β = 1.7; 95% CI: 0.4, 3.0), and PhenoAge acceleration (β = 2.1; 95% CI: 0.4, 3.8). In models stratified on social cohesion, associations of neighborhood poverty and quality with accelerated DNAm aging remained elevated for residents living in neighborhoods with lower social cohesion, but were null for those living in neighborhoods with higher social cohesion. Our study suggests that living in adverse neighborhood environments can speed up epigenetic aging, while positive neighborhood attributes may buffer effects.


[Surgical treatment of occlusive diseases of visceral branches of the abdominal aorta].
Sixty two patients having chronic circulatory disorders in visceral branches of the abdominal aorta were operated upon by the authors. An adequate circulation was restored as a result of reconstructive (44), conventionally reconstructive (14) and palliative (4) operations. A number of technics considerably facilitating these complicated reconstructive procedures are described: transaortic endarterectomy from the abdominal aorta, visceral branches and renal arteries: resection of the thoracoabdominal aorta followed by a plastic reconstruction of the celiac trunk ostium and others. In 47 patients (90.3%) a clinical effect was gained: the signs of ischemia of the digestive organs have disappeared.


Functional analysis of four CYP21 mutations from spanish patients with congenital adrenal hyperplasia.
Deleterious mutations in the CYP21 (steroid 21-hydroxylase) gene cause congenital adrenal hyperplasia (CAH). These mutations usually result from recombinations between CYP21 and an adjacent pseudogene, CYP21P, including deletions and transfers of deleterious mutations from CYP21P to CYP21 (gene conversions). Additional rare mutations that are not gene conversions account for 5-10% of 21-hydroxylase deficiency alleles. Recently, four novel CYP21 point mutations leading to amino acid changes were identified in a population of 57 Spanish families with CAH. A nonsense mutation, K74X, was also identified. The enzymatic activities of 21-hydroxylase mutants G90V, G178A, G291C, and R354H were examined in transiently transfected CHOP cells using progesterone and 17alpha-hydroxyprogesterone as substrates. The G90V, G291C, and R354H mutations effectively eliminated 21-hydroxylase activity. However, the G178A mutant retained significant activity when 17alpha-hydroxyprogesterone was the substrate. These results correlate well with the identification of G90V, G291C, and R354H in patients with severe "salt-wasting" disease and G178A in a patient with the milder simple virilizing form.


Direct live imaging of cell-cell protein transfer by transient outer membrane fusion in Myxococcus xanthus.
In bacteria, multicellular behaviors are regulated by cell-cell signaling through the exchange of both diffusible and contact-dependent signals. In a multicellular context, Myxococcus cells can share outer membrane (OM) materials by an unknown mechanism involving the traAB genes and gliding motility. Using live imaging, we show for the first time that transient contacts between two cells are sufficient to transfer OM materials, proteins and lipids, at high efficiency. Transfer was associated with the formation of dynamic OM tubes, strongly suggesting that transfer results from the local fusion of the OMs of two transferring cells. Last, large amounts of OM materials were released in slime trails deposited by gliding cells. Since cells tend to follow trails laid by other cells, slime-driven OM material exchange may be an important stigmergic regulation of Myxococcus social behaviors. DOI:http://dx.doi.org/10.7554/eLife.00868.001.


Diagnosis of Sjögren's syndrome in children.
We treated four children with clinical symptoms and laboratory findings suggestive of Sjögren's syndrome (SS). We also review the findings in 23 children with the diagnosis of SS whose cases were reported in the literature. We propose that the following criteria for the diagnosis of SS, which are mostly used in adults, should also be applied to children: (1) keratoconjunctivitis evidenced by a Schirmer test and a quantitative rose bengal test; (2) xerostomia shown by a decreased basal and stimulated salivary flow; (3) lymphocytic infiltration in a minor salivary gland biopsy specimen with at least two foci per 4 mm2; (4) laboratory evidence of a systemic autoimmune disorder on the basis of a rheumatoid factor of 1/160 or greater, antinuclear antibody of 1/160 or greater, or extractable nuclear antigen antibodies. Only close observation and long-term follow-up of these patients will allow a better insight in the natural history of SS in children. Those children who do not fulfill these diagnostic criteria also need close and prolonged follow-up study: one of the possibilities is that their conditions will ultimately evolve toward definite SS.


Doppler-echocardiographic assessment of the carbomedics supra-annular 'Top-Hat' prosthetic heart valve in the aortic position.
Twenty-one CarboMedics 'Top-Hat' bileaflet prostheses were implanted in the aortic position between May 1993 and May 1994 at our institution. Valve performance was assessed by repeat echocardiography. We found it very easy to implant this prosthesis even in the small aortic annulus and it allowed us to implant a valve that is at least one size larger than implantation in the intra-annular position allows. The only contraindication to the implantation of this prosthesis is when the coronary ostia are displaced downwards, which would apply to any supra-annular prosthesis. The Doppler echocardiographic assessment showed acceptable transvalvular gradients and velocity indexes. The Top-Hat prosthesis is now our valve of choice in the small aortic annulus.


Defining phenotypes and disease progression in sarcomeric cardiomyopathies: contemporary role of clinical investigations.
Mutations in cardiac sarcomere protein genes are associated with a variety of clinical phenotypes, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy as well as left ventricular non-compaction, with the overlap of morpho-functional manifestations in individual patients and families. Over time, initial phenotypes may undergo profound changes which determine clinical course and disease progression. Although genetic defects causing HCM and DCM have opposite effects at the myofilament level, a number of downstream maladaptive mechanisms, ranging from microvascular dysfunction and ischaemia to myocardial fibrosis and from diastolic dysfunction to abnormal sympathetic activation and arrhythmogenesis, seem to recur in sarcomeric cardiomyopathies, independent of the presenting phenotype. The extent and rate at which each of these features occur and evolve may be radically different in each form of cardiomyopathy, determining a clinical heterogeneity that is not only cross-sectional, but also longitudinal, i.e. time-related. Timely and sensitive detection of these long-term modifications in the clinical setting is a key to preventing advanced disease and identifying novel therapeutic targets. The present review evaluates the contribution of contemporary technology to pre-clinical diagnosis, characterization of phenotypes, and assessment of disease progression in sarcomere cardiomyopathies, including echocardiography, positron emission tomography, magnetic resonance, pathology, and circulating biomarkers.


Innovative endovascular technique for treatment of rare cause of haemoptysis in young.
A 17-year-old boy reported for evaluation of two episodes of massive haemoptysis. His clinical examination was unremarkable and investigations (haemogram, coagulogram, serological tests for connective tissue disorders) were normal. A 64-slice CT angiography revealed a saccular aneurysm of 3.8×3.7×3.3 cm arising from the right lower lobe pulmonary artery which was confirmed by cardiac catheterisation. The aneurysm was successfully blocked with a 16-14 Amplatzer duct occluder. A repeat CT angiogram performed after 15 days revealed the device in situ obliterating the aneurysm. Pulmonary artery aneurysm is an extremely rare cause of massive haemoptysis and indicates imminent rupture of the aneurysm which can be rapidly fatal. This case highlights the importance of using an innovative endovascular technique for treatment of a rare cause of haemoptysis.


Two cases of subacute thyroiditis after different types of SARS-CoV-2 vaccination.
Although the development of subacute thyroiditis (SAT) following viral infections is well-documented, the actual mechanism has not been clearly elucidated. The occurrence of SAT after vaccination has been reported in several case series and possible mechanisms such as molecular mimicry due to the exposure to viral proteins and/or abnormal reactogenicity by adjuvants have been implicated. We describe two cases who developed SAT three days after the messenger RNA vaccine against COVID-19 (Pfizer-BioNTech®) and six days after the inactivated COVID-19 vaccine (CoronaVac®). SAT diagnosis of these patients was delayed for more than two weeks. When the current cases were evaluated together with 1 Pfizer-BioNTech® and 3 CoronaVac® related cases reported previously, the patients were female aged between 30-42, except for the male patient we presented, and the complaints of the patients initiated within the first 2-7 days. While two Pfizer-BioNTech® vaccine-related cases were severely symptomatic and thyrotoxic at presentation, there were cases with mild to moderate clinical manifestations in CoronaVac® vaccine-related group. Physicians should be aware of SAT that may occur within a few days following the COVID-19 vaccination.


Carrying an unintended pregnancy to term and long-term maternal psychological distress: Findings from the Dutch prospective Amsterdam Born Children and their Development study.
Given the estimated high rate of unintended pregnancies, it is important to investigate long-term effects on psychological distress in women carrying an unintended pregnancy to term. However, research into associations between unintended pregnancies carried to term and psychological distress postpartum is mixed, and especially, evidence on long-term associations is scarce. To examine whether carrying an unintended pregnancy to term is associated with maternal psychological distress later in life, up to 12 years postpartum. This study is based on the population-based birth cohort study 'Amsterdam Born Children and their Development' study, which included pregnant people in 2003 (n = 7784) and followed them up until 12 years postpartum. Unintended pregnancy was measured as a multidimensional construct, based on self-reported data around 16 weeks gestation on pregnancy mistiming, unwantedness and unhappiness. Symptoms of maternal psychological distress were assessed around 3 months, 5 years and 12 years postpartum using multiple questionnaires measuring symptoms of depression, anxiety and stress. Multiple structural equation modelling models were analysed, examining the associations between dimensions of unintended pregnancy and maternal psychological distress per time point, while controlling for important co-occurring risks. Pregnancy mistiming and unhappiness were significant predictors of more maternal psychological distress around 3 months postpartum. Around 5 years postpartum, only pregnancy mistiming was positively associated with maternal psychological distress. Dimensions of unintended pregnancy were no longer associated with maternal psychological distress around 12 years postpartum. Strikingly, antenatal psychological distress was a much stronger predictor of maternal psychological distress than pregnancy intention dimensions. Those who carried a more unintended pregnancy to term reported more symptoms of psychological distress at 3 months and 5 years postpartum. People carrying an unintended pregnancy to term may benefit from extra support, not because of the pregnancy intentions per se, but because they may be related to antenatal psychological distress.


Non-invasive combined surrogates of remifentanil blood concentrations with relevance to analgesia.
Surrogates may provide easy and quick access to information about pharmacological parameters of interest that can be directly measured only with difficulty. Surrogates have been proposed for opioid blood concentrations to replace invasive sampling, serving as a basis for target-controlled infusion systems to optimize analgesia. We aimed at identifying surrogates of remifentanil steady-state blood concentrations with relevance for its clinical, in particular, analgesic, effects. A "single ascending dose" study design assessed concentration-dependent effects of remifentanil in a double-blind randomized fashion in 16 healthy volunteers. Remifentanil was administered by means of computerized infusion aimed at steady-state effect-site concentrations of 0, 1.2, 1.8, 2.4, 3, 3.6, 4.8, and 6 ng/ml (one concentration per subject, two subjects per concentration). Arterial remifentanil blood concentrations were measured during apparent steady state. Pharmacodynamic parameters were measured at baseline and during steady-state conditions. Potential surrogate parameters included the pupil diameter, the amplitude of pupil light reflex, and the performance in a visual tracking task. Clinical parameters were analgesia to experimental pain, nausea, tiredness, and visual acuity. Remifentanil blood concentrations were well predicted by its effects on the pupil light reflex amplitude, better than by its miotic effects. However, the best prediction for both remifentanil blood concentrations and analgesic effects was obtained using a combination of three surrogate parameters (pupil diameter, light reflex amplitude, and tracking performance). This combination of pharmacodynamic parameters provided even better predictions of analgesia than could be obtained using the measured opioid blood concentrations. Developing surrogates only for opioid blood concentrations is insufficient when opioid effects are the final goal. Combining pharmacodynamic surrogate parameters seems to provide a promising approach to obtain acceptable predictions of relevant clinical effects, with better results than obtained with measuring or estimating blood concentrations.


A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis.
Although the peripheral anti-inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti-inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti-inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation-based dopaminergic neurotoxicity models. In mice, NE-depleting toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected at 6 months of lipopolysaccharide (LPS)-induced neuroinflammation. It was found that NE depletion enhanced LPS-induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose-dependently protected dopaminergic neurons from LPS-induced neurotoxicity by inhibiting microglia activation and subsequent release of pro-inflammatory factors. However, NE-elicited neuroprotection was not totally abolished in cultures from β2-adrenergic receptor (β2-AR)-deficient mice, suggesting that novel pathways other than β2-AR are involved. To this end, It was found that submicromolar NE dose-dependently inhibited NADPH oxidase (NOX2)-generated superoxide, which contributes to the anti-inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (-) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS-induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism.


Human nicotinamide N-methyltransferase pharmacogenetics: gene sequence analysis and promoter characterization.
Nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and structurally related pyridines. NNMT enzymatic activity in human liver varies over a five-fold range with a bimodal frequency distribution - raising the possibility of regulation by a genetic polymorphism. We set out to characterize molecular genetic mechanisms that might be involved in the regulation of individual variation in human liver NNMT activity. After Northern blot analysis confirmed that NNMT is highly expressed in the liver, eight human hepatic biopsy samples, four each with 'low' or 'high' levels of activity, were used to perform quantitative Western blot analysis. There was a highly significant correlation (r(s) = 0.96, P < 0.0001) between NNMT activity and immunoreactive protein in these samples. We next determined that a potent promoter was located within the initial 700 bp of the 5'-flanking region of the human NNMT gene. That gene consists of 3 exons, with an initial 1240 bp intron and a second intron that is approximately 14 kb in length. We subsequently isolated DNA from 27 human liver biopsy samples with low, intermediate or high levels of NNMT activity. The three exons, all 1240 bp of intron 1 and approximately 700 bp of the 5'-flanking region of the NNMT gene were amplified from each of these samples with the polymerase chain reaction, followed by DNA sequencing to identify genetic polymorphisms that might correlate with 'NNMT phenotype'. No single nucleotide polymorphisms (SNPs) or insertion/deletion events were detected within either the exons or 5'-flanking regions of NNMT for these 27 samples. Although there were eight SNPs within intron 1, none were systematically related to level of NNMT activity. These results indicate that the exons and 5'-flanking region of the NNMT gene display little or no sequence variation. Therefore, polymorphisms within these areas of the gene are unlikely to be related to wide individual variations in the level of this enzyme activity in the human liver.


[Urgent problems in the study of pyelonephritis in children].
The literature data and own observations concerning the features of patho- and morphogenesis of pyelonephritis in children are presented. Particular attention is given to the importance of renal tissue and intrarenal blood vessels dysplasia in the genesis and development of pyelonephritis as well as to the pathogenetic role of inflammatory processes in urinary tract wall in obstructive uropathies. The importance of morphological studies in diagnosis, prophylaxis and treatment of pyelonephritis in children is emphasized.


Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma.
The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL). To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management. In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium. (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion. The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients. POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.


[Ultrasonography in differential diagnosis of focal liver neoplasms].
Results of diagnosis and treatment of 2576 patients with focal lesions of the liver are analyzed. Differential ultrasound characteristics for all studied types of liver focal lesions are worked out. The effectiveness of the ultrasound investigation amounted for echinococcosis 91-95%, non-hydatid cysts--95.5%, hepatic tumors--99%, hepatic abscesses--87% and for the hemangioma of the liver--76.3%.


Thinking While Moving or Moving While Thinking - Concepts of Motor-Cognitive Training for Cognitive Performance Enhancement.
The demographic change in industrial countries, with increasingly sedentary lifestyles, has a negative impact on mental health. Normal and pathological aging leads to cognitive deficits. This development poses major challenges on national health systems. Therefore, it is necessary to develop efficient cognitive enhancement strategies. The combination of regular physical exercise with cognitive stimulation seems especially suited to increase an individual's cognitive reserve, i.e., his/her resistance to degenerative processes of the brain. Here, we outline insufficiently explored fields in exercise-cognition research and provide a classification approach for different motor-cognitive training regimens. We suggest to classify motor-cognitive training in two categories, (I) sequential motor-cognitive training (the motor and cognitive training are conducted time separated) and (II) simultaneous motor-cognitive training (motor and cognitive training are conducted sequentially). In addition, simultaneous motor-cognitive training may be distinguished based on the specific characteristics of the cognitive task. If successfully solving the cognitive task is not a relevant prerequisite to complete the motor-cognitive task, we would consider this type of training as (IIa) motor-cognitive training with additional cognitive task. In contrast, in ecologically more valid (IIb) motor cognitive training with incorporated cognitive task, the cognitive tasks are a relevant prerequisite to solve the motor-cognitive task. We speculate that incorporating cognitive tasks into motor tasks, rather than separate training of mental and physical functions, is the most promising approach to efficiently enhance cognitive reserve. Further research investigating the influence of motor(-cognitive) exercises with different quantitative and qualitative characteristics on cognitive performance is urgently needed.


Aflatoxin and the Etiology of Liver Cancer and Its Implications for Guatemala.
During the 60 years since the first scientific reports about a relation between aflatoxin exposure and adverse health consequences, both in animals and humans, there has been a remarkable number of basic, clinical and population science studies characterizing the impact of this mycotoxin on diseases such as liver cancer. Many of these human investigations to date have focused on populations residing in Asia and Africa due to the high incidence of liver cancer and high exposures to aflatoxin. These studies formed the basis for the International Agency for Research on Cancer to classify the aflatoxins as Group 1 known human carcinogens. In addition, aflatoxin contamination levels have been used in international commodity trade to set the price of various staples such as maize and groundnuts. While there have been many case-control and prospective cohort studies of liver cancer risk over the years there have been remarkably few investigations focused on liver cancer in Latin America. Our interdisciplinary and multiple institutional collaborative has been developing a long-term strategy to characterize the role of aflatoxin and other mycotoxins as health risk factors in Guatemala and neighboring countries. This paper summarizes a number of the investigations to date and provides a roadmap of our strategies for the near term to discern the emergent etiology of liver cancer in this region. With these data in hand public health-based prevention strategies could be strategically implemented and conducted to lower the impact of these mycotoxins on human health.


Expression of a novel P22 ORFan gene reveals the phage carrier state in Salmonella typhimurium.
We discovered a novel interaction between phage P22 and its host Salmonella Typhimurium LT2 that is characterized by a phage mediated and targeted derepression of the host dgo operon. Upon further investigation, this interaction was found to be instigated by an ORFan gene (designated pid for phage P22 encoded instigator of dgo expression) located on a previously unannotated moron locus in the late region of the P22 genome, and encoding an 86 amino acid protein of 9.3 kDa. Surprisingly, the Pid/dgo interaction was not observed during strict lytic or lysogenic proliferation of P22, and expression of pid was instead found to arise in cells that upon infection stably maintained an unintegrated phage chromosome that segregated asymmetrically upon subsequent cell divisions. Interestingly, among the emerging siblings, the feature of pid expression remained tightly linked to the cell inheriting this phage carrier state and became quenched in the other. As such, this study is the first to reveal molecular and genetic markers authenticating pseudolysogenic development, thereby exposing a novel mechanism, timing, and populational distribution in the realm of phage-host interactions.


Ecophysiology of the Actinobacteria in activated sludge systems.
This review considers what is known about the Actinobacteria in activated sludge systems, their abundance and their functional roles there. Participation in processes leading to the microbiological removal of phosphate and in the operational problems of bulking and foaming are discussed in terms of their ecophysiological traits. We consider critically whether elucidation of their nutritional requirements and other physiological properties allow us to understand better what might affect their survival capabilities in these highly competitive systems. Furthermore, how this information might allow us to improve how these processes work is discussed.


Tardive dyskinesia: nondopaminergic treatment approaches.
The continuing concern about tardive dyskinesia (TD) has stimulated a broad search for therapies for this disorder. Since neuroleptic drugs are thought to be the etiological agents, acting presumably through dopamine receptor blockade, nondopaminergic drugs have been the focus of recent study. However, no uniformly safe and effective drug treatment has been identified. Augmentation of cholinergic function is theoretically attractive, but further research is needed to develop practical and effective compounds. GABA drugs do not consistently suppress TD. The effect of benzodiazepines in TD is unclear, but these agents may be of some temporary benefit in patients with distressing symptoms. Lithium, serotonergic compounds, and numerous neuropeptides all fail to have any consistent effect in TD. Early reports of benefit with alpha- and beta-noradrenergic agents are interesting but require further study. Many other drug types have been tried without benefit. For the majority of patients, it may be best to give no drug treatment. Any drug that is capable of suppressing TD may aggravate the disorder in the long term. The potential for a spontaneous gradual remission of TD is an argument in favor of a patient, nonaggressive, and cautiously optimistic approach to this disorder.


Alcohol dehydrogenase 3 genotype modification of the association of alcohol consumption with breast cancer risk.
Because alcohol dehydrogenase 3 (ADH3) is rate-limiting in alcohol oxidation and is polymorphic, we examined ADH3 genotype in relation to alcohol intake and breast cancer risk. We conducted a case-control study among Caucasian women aged 40-85 with incident, pathologically confirmed breast cancer and controls, frequency-matched on age and county. Queries included alcohol intake in the past 20 years. Genomic DNA was genotyped for the exon VIII ADH polymorphism by PCR followed by restriction enzyme digestion. Computation of odds ratios (OR) and 95% confidence intervals (CI) was by unconditional logistic regression. We found increased risk among pre- (OR 2.3, 95%, CI 1.2-4.3) but not postmenopausal women (OR 1.1, 95% CI 0.7-1.7) associated with ADH3(1-1) compared to ADH3(1-2) and ADH3(2-2) genotypes. Risk was increased for premenopausal women with the ADH3(1-1) genotype and alcohol intake above the median (OR 3.6, 95% CI 1.5-8.8) compared to lighter drinkers with the ADH3(2-2) or ADH3(1-2) genotypes. ORs were close to null for premenopausal women in other drinking and genotype groups and for postmenopausal women categorized by genotype and alcohol consumption. Among premenopausal women there may be a group more genetically susceptible to an alcohol consumption effect on breast cancer risk.


Storing summary patient data as a microcomputer file.
The time taken to summarize 1000 patient records and store this data as a hard disc file on a microcomputer was evaluated in a health centre with about 7300 patients. On average it took 25 minutes to prepare or update summary sheets for each patient and between three to five minutes to input the data to the computer. About one in 10 of the records were long and complicated and took considerably more time to summarize. An error rate of 9% over six months was determined for the age-sex register, mostly owing to patients who had left the practice. In about 5% of cases important information was missing from the A4 folders and was only obtainable from the health visitor records.


Chronic stress model simulated by salbutamol promotes tumorigenesis of gastric cancer cells through β2-AR/ERK/EMT pathway.
Chronic stress induced by long-term anxiety and depression can promote the malignant progression of gastric cancer. β2-adrenergic receptor (β2-AR) is a critical mediator for chronic stress-induced multiple processes of tumor cells. However, the function of chronic stress in gastric cancer and its potential mechanisms in vivo and in vitro, especially at the cellular level, remain unknown. Here, we provide further evidence that chronic stress affected behavior and hypothalamus pituitary adrenal axis related hormone levels in mice. Furthermore, immunofluorescence showed that emotion affected the expression of epithelial-mesenchymal transition (EMT) markers in patients' tissues. To address this, salbutamol, a specific agonist of β2-AR, was utilized for simulating chronic stress and demonstrating the mechanism of stress in tumor progression at the molecular level both in vivo and in vitro. Salbutamol significantly induced EMT, migration and invasion via ERK (Extracellular-signal-regulated kinase) phosphorylation, and the effects were reversed by the β2-AR antagonist ICI-118,551. The promoting effects of salbutamol on EMT, migration and invasion were inhibited by phosphorylation inhibitor of ERK PD98059 in vitro. Analysis of xenograft models revealed that salbutamol significantly promoted tumor growth and adrenal volume, while ICI-118,551 inhibited these effects. In addition, salbutamol increased the expression of mesenchymal marker N-cadherin and decreased epithelial marker E-cadherin in transplanted tumor tissue. In conclusion, salbutamol simulates a chronic stress model, which promotes tumorigenesis of gastric cancer cells through β2-AR/ERK/EMT pathway.


Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene.
Expression of the CD4 and CD8 glycoproteins is a tightly regulated process tied to the maturation of functionally distinct classes of thymocytes. Therefore, understanding of the mechanism of expression of the genes encoding CD4 and CD8 is likely to yield important insight into regulation of the differentiated functions of T cells. Here, we report the identification of a T-cell-specific enhancer in a DNase I-hypersensitive region about 13 kb 5' of the transcription initiation site of the murine CD4 gene. Within the minimal enhancer element, at least three nuclear protein binding sites were identified by DNase I footprint analysis. One site contains the consensus motif for TCF-1 alpha/LEF-1, a recently identified HMG box transcription factor primarily expressed in pre-B and T cells. By Southwestern (DNA-protein) blotting and binding competition analyses, the protein binding to this site was found to be indistinguishable from TCF-1 alpha/LEF-1. Mutagenesis of this site resulted in loss of factor binding but had a relatively minor effect on enhancer activity. In contrast, mutations in another site, containing two consensus binding motifs for basic helix-loop-helix proteins, abolished factor binding and dramatically reduced enhancer activity. None of the protein binding sites had activity on its own, suggesting that the CD4 enhancer requires the interaction of multiple regulatory sites.


Osteoporosis and Fracture Risk Following Benign Hysterectomy Among Female Patients in Korea.
Prior research about the association between hysterectomy and osteoporosis risk had limitations. To assess osteoporosis and fracture risk among female patients who underwent hysterectomy due to benign conditions. In this retrospective cohort study, female patients aged 40 to 59 years with benign hysterectomy between 2003 and 2011 were selected from Korean National Health Insurance Data and matched by 1:1 propensity score with female patients who had health checkups and indicated that they had not had a hysterectomy. A Cox proportional hazard model was used to analyze osteoporosis and fracture risk, with participants monitored until December 31, 2020. Data analysis was performed from July 16, 2022, to January 12, 2023. Hysterectomy with or without adnexal surgical procedure. The primary outcome was the risk of osteoporosis. Secondary outcomes included the risk of vertebral fracture, hip fracture, other fractures, and total fracture. The study population included 25 910 patients; the median (IQR) age was 47 (44-50) years, and median (IQR) follow-up period was 10.9 (9.4-12.7) years. In the stratified-extended Cox proportional analysis, female patients who underwent hysterectomy without an adnexal surgical procedure were associated with a higher risk of osteoporosis within 7 years compared with female patients who did not undergo hysterectomy (hazard ratio [HR], 1.28 [95% CI, 1.19-1.37]); the analysis was divided into 7 years due to a violation of the Cox assumption, and the risk did not differ after 7 years (HR, 0.99 [95% CI, 0.93-1.06]). However, the hysterectomy group with an adnexal surgical procedure had an association with higher risk of osteoporosis compared with the nonhysterectomy group both within 7 years of study entry (HR, 1.56 [95% CI, 1.33-1.82]) and after 7 years (HR, 1.20 [95% CI, 1.04-1.40]). In the hysterectomy group without an adnexal surgical procedure, the risks of vertebral fracture, hip fracture, and total fracture were similar to those in the nonhysterectomy group. Similar trends were observed in the hysterectomy group with an adnexal surgical procedure. Hysterectomy without an adnexal surgical procedure was associated with an increased osteoporosis risk within 7 years, but not afterwards, compared with the nonhysterectomy group. Hysterectomy was not associated with vertebral and hip fractures.


Movement patterns of stream-dwelling fishes from Mata Atlântica, Southeast Brazil.
The identification of mechanisms of spatial-temporal variation, obtained from the quantification of natural populations, is a central topic of ecological research. Despite its importance to life-history theory, as well as to conservation and management of natural populations, no studies concerning movement patterns and home range of small stream-dwelling fishes from Brazilian rain forests are known. In the present study we aimed to describe the longitudinal pattern of long distance movement as well as local patterns of short movement (daily home-range) of fishes from a Mata Atlântica stream from Southeast Brazil. We gathered information about movement dynamic in order to discuss the relationship between swimming ability, fish morphology and home range. Long distance movement data were obtained in a mark-recapture experiment held in the field between June and September - 2008, on five sites along the Ubatiba stream. For this study, we had one day to mark fishes, on June-19, and 14 events for recapture. Considering the ten species that inhabit the study area, our study showed that four species: Astyanax janeiroensis, Astyanax hastatus, Parotocinclus maculicauda and Pimelodella lateristriga, moved at least 6 000m in 60 days. The other six species did not present long distance movements, as they were recaptured in the same site 90 days after being marked. For short distance study, movement data were obtained in one mark-recapture experiment held in a 100m long site subdivided into five 20m stretches where fishes were marked with different elastomer colours. We marked 583 specimens that after recapture showed two groups of different movement patterns. The first group was called "Long Movement Group" and the second one was called "Short Movement Group". The Long Movement Group showed, on average, 89.8% of moving fishes and 10.2% of non moving fishes, against 21.3% and 78.7%, respectively, for the Short Movement Group. It was concluded that fish movement could explain the previously mentioned community stability, and that it is correlated to specific morphological attributes.


Data-Driven Finite-Horizon Approximate Optimal Control for Discrete-Time Nonlinear Systems Using Iterative HDP Approach.
This paper presents a data-based finite-horizon optimal control approach for discrete-time nonlinear affine systems. The iterative adaptive dynamic programming (ADP) is used to approximately solve Hamilton-Jacobi-Bellman equation by minimizing the cost function in finite time. The idea is implemented with the heuristic dynamic programming (HDP) involved the model network, which makes the iterative control at the first step can be obtained without the system function, meanwhile the action network is used to obtain the approximate optimal control law and the critic network is utilized for approximating the optimal cost function. The convergence of the iterative ADP algorithm and the stability of the weight estimation errors based on the HDP structure are intensively analyzed. Finally, two simulation examples are provided to demonstrate the theoretical results and show the performance of the proposed method.


Central Diabetes Insipidus in Refractory Antineutrophil Cytoplasmic Antibody-associated Vasculitis.
We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.


Globally altered sleep patterns and physical activity levels by confinement in 5056 individuals: ECLB COVID-19 international online survey.
Symptoms of psychological distress and disorder have been widely reported in people under quarantine during the COVID-19 pandemic; in addition to severe disruption of peoples' daily activity and sleep patterns. This study investigates the association between physical-activity levels and sleep patterns in quarantined individuals. An international Google online survey was launched in April 6th, 2020 for 12-weeks. Forty-one research organizations from Europe, North-Africa, Western-Asia, and the Americas promoted the survey through their networks to the general society, which was made available in 14 languages. The survey was presented in a differential format with questions related to responses "before" and "during" the confinement period. Participants responded to the Pittsburgh Sleep Quality Index (PSQI) questionnaire and the short form of the International Physical Activity Questionnaire. 5056 replies (59.4% female), from Europe (46.4%), Western-Asia (25.4%), America (14.8%) and North-Africa (13.3%) were analysed. The COVID-19 home confinement led to impaired sleep quality, as evidenced by the increase in the global PSQI score (4.37 ± 2.71 before home confinement vs. 5.32 ± 3.23 during home confinement) (p < 0.001). The frequency of individuals experiencing a good sleep decreased from 61% (n = 3063) before home confinement to 48% (n = 2405) during home confinement with highly active individuals experienced better sleep quality (p < 0.001) in both conditions. Time spent engaged in all physical-activity and the metabolic equivalent of task in each physical-activity category (i.e., vigorous, moderate, walking) decreased significantly during COVID-19 home confinement (p < 0.001). The number of hours of daily-sitting increased by ~2 hours/days during home confinement (p < 0.001). COVID-19 home confinement resulted in significantly negative alterations in sleep patterns and physical-activity levels. To maintain health during home confinement, physical-activity promotion and sleep hygiene education and support are strongly warranted.


Rhesus macaque milk: magnitude, sources, and consequences of individual variation over lactation.
Lactation represents the greatest postnatal energetic expenditure for mammalian mothers, and a mother's ability to sustain the costs of lactation is influenced by her physical condition. Mothers in good condition may produce infants who weigh more, grow faster, and are more likely to survive than the infants of mothers in poor condition. These effects may be partially mediated through the quantity and quality of milk that mothers produce during lactation. However, we know relatively little about the relationships between maternal condition, milk composition, milk yield, and infant outcomes. Here, we present the first systematic investigation of the magnitude, sources, and consequences of individual variation in milk for an Old World monkey. Rhesus macaques produce dilute milk typical of the primate order, but there was substantial variation among mothers in the composition and amount of milk they produced and thus in the milk energy available to infants. Relative milk yield value (MYV), the grams of milk obtained by mammary evacuation after 3.5-4 h of maternal-infant separation, increased with maternal parity and was positively associated with infant weight. Both milk gross energy (GE) and MYV increased during lactation as infants aged. There was, however, a trade-off; those mothers with greater increases in GE had smaller increases in MYV, and their infants grew more slowly. These results from a well-fed captive population demonstrate that differences between mothers can have important implications for milk synthesis and infant outcome.


Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets.
Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.


Navigating through the r packages for movement.
The advent of miniaturized biologging devices has provided ecologists with unprecedented opportunities to record animal movement across scales, and led to the collection of ever-increasing quantities of tracking data. In parallel, sophisticated tools have been developed to process, visualize and analyse tracking data; however, many of these tools have proliferated in isolation, making it challenging for users to select the most appropriate method for the question in hand. Indeed, within the r software alone, we listed 58 packages created to deal with tracking data or 'tracking packages'. Here, we reviewed and described each tracking package based on a workflow centred around tracking data (i.e. spatio-temporal locations (x, y, t)), broken down into three stages: pre-processing, post-processing and analysis, the latter consisting of data visualization, track description, path reconstruction, behavioural pattern identification, space use characterization, trajectory simulation and others. Supporting documentation is key to render a package accessible for users. Based on a user survey, we reviewed the quality of packages' documentation and identified 11 packages with good or excellent documentation. Links between packages were assessed through a network graph analysis. Although a large group of packages showed some degree of connectivity (either depending on functions or suggesting the use of another tracking package), one third of the packages worked in isolation, reflecting a fragmentation in the r movement-ecology programming community. Finally, we provide recommendations for users when choosing packages, and for developers to maximize the usefulness of their contribution and strengthen the links within the programming community.


Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis: have you checked the ovaries?
Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune disorder that can occur as a paraneoplastic phenomenon related to ovarian teratomas. It is a serious but reversible condition with improved outcomes following prompt tumor removal. We report two cases from our recent experience. In the first case a small poorly described lesion, confirmed as a teratoma only at histology, was managed by laparoscopic oopohorectomy. In the second case a large teratoma was managed by laparoscopic cystectomy. Postoperatively both women made a good recovery. Gynecologists may be called upon to perform ovarian surgery outside of normal surgical indications, in young women who will often lack capacity to consent. Fertility-sparing ovarian cystectomy is possible in some cases, but will be challenging for small deeply buried tumors. Blind bilateral oophorectomy has been performed successfully in extreme cases. Information of the benefit of ovarian surgery will be essential to the surgeon during preoperative counseling.