Effects of 17beta-estradiol, 4-nonylphenol and PCB 126 on the estrogenic activity and phase 1 and 2 biotransformation enzymes in male sea bass (Dicentrarchus labrax).
The endocrine system of wildlife is exposed to a wide variety of natural and man-made chemicals which may lead to damage to the reproductive system and other adverse effects, including alteration of drug-metabolizing enzymes. In the present study, the effects of in vivo exposure to a natural (17beta-estradiol: E2) or a xenoestrogen (4-nonylphenol: NP) estrogen or an anti-estrogen (3,3',4,4',5-pentachlorobiphenyl: PCB 126) upon vitellogenin (VTG) synthesis and hepatic phase 1 and 2 enzymes have been investigated in adult male sea bass. By means of ELISA analysis with the use of polyclonal antibodies prepared against VTG purified from E2-treated sea bass, we assessed the time course and sensitivity of VTG induction in the plasma of sea bass treated with E2 at 0.1, 0.5, 2.5 and 5.0 mg/kg doses or NP at 5.0 or 50 mg/kg doses, respectively. Sea bass sensitivity to this induction was found to be similar to that of other fish species, but with a delay in maximal response. E2 treatment also caused a selective time- and dose-dependent inhibition of hepatic CYP1A-linked EROD and phase 2 glutathione S-transferase (GST) activities, without affecting the activity of CYP3A-linked 6beta-testosterone hydroxylase, (omega)- and (omega-1)-lauric acid hydroxylases or phase 2 DT-diaphorase. A similar selective inhibition on CYP1A was also observed in fish treated with 50 mg/kg NP. The results regarding CYP1A and CYP3A were also confirmed by Western blot analysis. When the sea bass were treated with either 10 or 100 microg/kg PCB 126, an AhR ligand not yet tested in vivo in fish to assess its anti-estrogenicity, a modest and selective induction of EROD and DT-diaphorase activities was observed. Interestingly, both these activities were recovered to their control levels in sea bass co-treated with 0.5 mg/kg E2 and 10 or 100 microg/kg PCB 126, probably through a cross-talk mechanism between the estrogen receptor and AhR or other transcription factors that regulate the expression of these enzymes. Furthermore, it was demonstrated that PCB 126 possesses a potent anti-estrogenic activity in the sea bass in vivo as it inhibited the E2-induced VTG synthesis with an IC50 of 28 microg/kg. The results of this study suggest that the exposure of fish to xenoestrogens or anti-estrogens may alter, in addition to various physiological processes, the expression of specific CYPs and phase 2 enzymes, thereby reducing the capability of their detoxication system.


Drying polymeric drug-loaded nanocapsules: the wet granulation process as a promising approach.
The industrial development of polymeric nanoparticle suspensions is still limited due to their low physicochemical stability. In this paper, we evaluated the wet granulation process as an alternative method to dry polymeric nanocapsules using dexamethasone as drug model. Nanocapsule suspensions were used as granulating liquid as well as a drug-loaded-nanocarrier in the wet granulation process. Granules were evaluated regarding their drug content, mean particle size, yield, moisture content, flow properties, stability on storage, recovery studies after water redispersion and morphological characteristics (SEM). Granules containing dexamethasone-loaded polymeric nanocapsules presented good drug content (approximately 94%) and were stable for 6 months at room temperature. Morphological analyses showed nanostructures on their surface and the nanoparticles were recovered after redispersing the granules in water. These results suggest that wet granulation can be an interesting alternative to dry drug-loaded nanocapsule suspensions.


A mode of selective action of thiadiazolyl urea herbicides.
1,1-Dimethyl-3-(5-tert-butyl-1,3,4-thiadiazol-2-yl)urea(I) was newly synthesized by the authors. (I) was found to have the strongest herbicidal activities among the thiadiazolylurea derivatives and selectivity of (I) was found between barley (tolerant)and wheat (susceptible) plants. Neither absorption by roots nor translocation from roots to shoots of 35S-labeled (I) in barley and wheat correlated with selectively between these species of plants. (I) was metabolized in both species of plants by N-demethylation to 1-methyl-3-(5-tert-butyl-1,3,4-thiadiazol-2-yl)urea(II), and further to non-phytotoxic 3-(5-tert-butyl-1,3,4-thiadiazol-2-yl)urea(III). The rates of the N-demethylating reactions from (I) to (II) and from (II) to (III) were much greater in barley shoots than in wheat shoots, especially in the second demethylation. It was concluded that the selective activity of (I) between barley and wheat plants was mainly due to the difference in rates of N-demethylation of (I). In addition, it was found that cotton plants, well known as tolerant to phenylurea herbicides, were remarkably susceptible to (I). It was indicated that different rates of the N-demethylating reaction between the phenyl and thiadiazolyl herbicides correlated with susceptibility to them.


Nanomagnetic Elastomers for Realizing Highly Responsive Micro- and Nanosystems.
Evolution has produced natural systems that generate motion and sense external stimuli at the micro- and nanoscales. At extremely small scales, the intricate motions and large deformations shown by these biosystems are due to a tipping balance between their structural compliance and the actuating force generated in them. Artificially mimicking such ingenious systems for scientific and engineering applications has been approached through the development and use of different smart materials mostly limited to microscale dimensions. To push the application range down to the nanoscale, we developed a material preparation process that yields a library of nanomagnetic elastomers with high magnetic particle concentrations. Through this process, we have realized a material with the highest magnetic-to-elastic force ratio, as is shown by an extensive mechanical and magnetic characterization of the materials. Furthermore, we have fabricated and actuated micro- and nanostructures mimicking cilia, demonstrating the extreme compliance and responsiveness of the developed materials.


Lattice density functional theory of molecular diffusion.
A density functional theory of diffusion is developed for lattice fluids with molecular flux as a functional of the density distribution. The formalism coincides exactly with the generalized Ono-Kondo density functional theory when there is no gradient of chemical potential, i.e., at equilibrium. Away from equilibrium, it gives Fick's first law in the absence of a potential energy gradient, and it departs from Fickian behavior consistently with the Maxwell-Stefan formulation. The theory is applied to model a nanopore, predicting nonequilibrium phase transitions and the role of surface diffusion in the transport of capillary condensate.


IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation.
T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-alpha. Analysis of the in vivo effects of IFN-gamma in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-beta signaling in T cells - reveals that the net effect of IFN-gamma in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-gamma has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-gamma signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.


FMCW Laser Fuze Multiple Scattering Model and Accurate Fixed-Distance Algorithm in a Smoke Environment.
In a smoke environment, suspended particles can scatter and absorb laser photons, making target echo signals extremely weak and difficult to extract and identify, which causes obvious difficulty in fixed-distance of laser fuze. In this paper, the multiple scattering model of frequency-modulated-continuous-wave (FMCW) laser fuze in a smoke environment was established. This model simulates multi-path propagation and multiple scattering of photons. At the same time, we use the correntropy spectral density (CSD) algorithm for accurate fixed-distance of FMCW laser fuze. The absolute error of distance does not exceed 0.15 m in smoke interference environment.


Associations between parenting styles and children's fruit and vegetable intake.
This study investigated associations between children's fruit and vegetable intake and their parents' parenting style (i.e., authoritative: high warmth-high control; authoritarian: low warmth-high control; permissive: high warmth-low control; and disengaged: low warmth-low control). Data from the Longitudinal Study of Australian Children K cohort, comprising approximately 5,000 children, were used for analyses in wave 1 (4-5 years), wave 2 (6-7 years), and wave 3 (8-9 years). Fruit and vegetable intake patterns were extracted through exploratory factor analysis. Boys with authoritarian mothers were found less likely to consume fruits and vegetables at 6-9 years. Children of both genders with authoritative and permissive fathers, and girls with authoritative mothers at 4-5 years were found most likely to consume fruits and vegetables two and four years later. Exploring possible mechanisms underlying such associations may lead to interventions aimed at increasing children's consumption of fruits and vegetables.


Novel terpenoids, trichoderonic acids A and B isolated from Trichoderma virens, are selective inhibitors of family X DNA polymerases.
Trichoderonic acids A (1) and B (2), novel terpenoids, and (+)-heptelidic acid (3) isolated from cultures of a fungus, Trichoderma virens, and their structures were identified by spectroscopic analysis. These compounds selectively and competitively inhibited the activities of mammalian DNA polymerases beta, lambda (pols beta, lambda), and terminal deoxynucleotidyl transferase (TdT) in family X of pols, and compound 2 was a stronger inhibitor than compound 1 or 3. On the other hand, compounds 1-3 did not influence the activities of the other families (A-, B-, and the Y-families) of the mammalian pols tested, and showed no effect on the activities of plant pol alpha, fish pol delta, prokaryotic pol, or the other DNA metabolic enzymes tested. Compound 2 suppressed the growth of two human cancer cell lines, cervix carcinoma cells (HeLa) and breast carcinoma cells (MCF-7). The results suggest that these compounds identified inhibition among the families of mammalian pols.


Prevalence and clinical hallmarks of primary exercise headache in middle-aged Japanese on health check-up.
Objective We examined the prevalence and clinical features of primary exercise headache (PEH) in middle-aged Japanese population. Methods A headache specialist interviewed middle-aged subjects serially on health check-up. The primary headaches were diagnosed according to the International Classification of Headache Disorders (ICHD-III beta). Cardiovascular disease (CVD) risk and radiological findings were analyzed. Prevalence of PEH and clinical features were assessed. Results Among 2,546 subjects (1,588 men and 958 women), thirty subjects (13 men and 17 women) were diagnosed with PEH. The prevalence of PEH was 1.19%, 0.82% in men and 1.77% in women. The mean age [standard deviation (SD)] of the subjects was 44.3 (8.8) years and their mean duration (SD) of PEH was 4.5 (7.0) months. Headache occurred bilaterally (23 patients) or unilaterally (7 patients), and in the occipital (16 patients), frontal (10 patients) or diffuse region (4 patients). The persistent headache time ranged from 5 minutes to 12 hours. The degree of headache severity was classified as mild (13 patients), moderate (5 patients) or severe degree (12 patients). PEH was triggered by gym training (16 patients), swimming (6 patients), running (6 patient) and skiing (2 patients). All patients were exercise beginners or played a sport occasionally. No patients visited physicians for headache consultation. Other primary headaches coexisted in 20 patients (67%). Twenty patients had migraine without aura (MO). Seven patients had headache associated with sexual activity. Five patients had cough headache. Two patients had CVD risk factors. Conclusion The present study of PEH indicated the prevalence of 1.2% and the female/male ratio of 2.1 in middle-aged Japanese. The comorbidity rate of MO was high. PEH may not be an uncommon headache in middle-aged MO sufferers and sport beginners.


Applicability of droplet digital polymerase chain reaction for minimal residual disease monitoring in Philadelphia-positive acute lymphoblastic leukaemia.
In Ph+ acute lymphoblastic leukaemia (Ph+ ALL), minimal residual disease (MRD) is the most relevant prognostic factor. Currently, its evaluation is based on quantitative real-time polymerase chain reaction (Q-RT-PCR). Digital droplet PCR (ddPCR) was successfully applied to several haematological malignancies. We analyzed 98 samples from 40 Ph+ ALL cases, the majority enrolled in the GIMEMA LAL2116 trial: 10 diagnostic samples and 88 follow-up samples, mostly focusing on positive non-quantifiable (PNQ) or negative samples by Q-RT-PCR to investigate the value of ddPCR for MRD monitoring. DdPCR BCR/ABL1 assay showed good sensitivity and accuracy to detect low levels of transcripts, with a high rate of reproducibility. The analysis of PNQ or negative cases by Q-RT-PCR revealed that ddPCR increased the proportion of quantifiable samples (p < 0.0001). Indeed, 29/54 PNQ samples (53.7%) proved positive and quantifiable by ddPCR, whereas 13 (24.1%) were confirmed as PNQ by ddPCR and 12 (22.2%) proved negative. Among 24 Q-RT-PCR-negative samples, 13 (54.1%) were confirmed negative, four (16.7%) resulted PNQ and seven (29.2%) proved positive and quantifiable by ddPCR. Four of 5 patients, evaluated at different time points, who were negative by Q-RT-PCR and positive by ddPCR experienced a relapse. DdPCR appears useful for MRD monitoring in adult Ph+ ALL.


FURIN gene variants (rs6224/rs4702) as potential markers of death and cardiovascular traits in severe COVID-19.
Furin is a protease that plays a key role in the infection cycle of SARS-CoV-2 by cleaving the viral proteins during the virus particle assembly. In addition, Furin regulates several physiological processes related to cardio-metabolic traits. DNA variants in the FURIN gene are candidates to regulate the risk of developing these traits as well as the susceptibility to severe COVID-19. We genotyped two functional FURIN variants (rs6224/rs4702) in 428 COVID-19 patients in the intensive care unit. The association with death (N = 106) and hypertension, diabetes, and hyperlipidaemia was statistically evaluated. The risk of death was associated with age, hypertension, and hypercholesterolemia. The two FURIN alleles linked to higher expression (rs6224 T and rs4702 A) were significantly increased in the death cases (odds ratio= 1.40 and 1.43). Homozygosis for the two high expression genotypes (rs6224 TT and rs4702 AA) and for the T-A haplotype was associated with an increased risk of hypercholesterolemia. In the multiple logistic regression both, hypercholesterolemia and the TT + AA genotype were significantly associated with death. In conclusion, besides its association with hypercholesterolemia, FURIN variants might be independent risk factors for the risk of death among COVID-19 patients.


Short-term outcomes after percutaneous coronary intervention: effects of stenting and institutional volume shifts.
This study examines how the dissemination of stenting and procedural shifts to high-volume facilities have affected short-term outcomes after percutaneous coronary intervention (PCI). Discharge information from the 1994 and 1997 US Nationwide Inpatient Sample was used. Data from 1994 involved 84,036 angioplasties, 27.3% of which were performed for acute myocardial infarction (AMI), at a time when stents were generally unavailable. Data from 1997 included 118,548 angioplasties, 30.2% of which were performed for AMI and 59% of which involved stenting. Outcomes included same-admission mortality and same-admission bypass grafting surgery (CABG). Compared with 1994, in 1997 stents were in widespread use, and there was a significant shift in PCI procedures to high-volume facilities. There was no significant difference in overall mortality rates between 1994 and 1997. However, same-admission CABG rates were lower in 1997 than in 1994 for the AMI group (2.9% vs 4.7%, P <.0001) and for the no-AMI group (1.8% vs 3.0%, P <.0001), which was attributable almost entirely to stenting. For 1997 only, patients receiving stents had a lower mortality rate than patients undergoing PCI without stenting (AMI 2.7% vs 4.7%, P <.0001, no AMI 0.7% vs 0.9%, P =.004). Despite the dissemination of stenting and shifts to high-volume facilities, overall mortality rates after PCI have not significantly changed. However, patients undergoing stenting in 1997 had a significantly lower mortality rate than patients who did not undergo stenting, suggesting that stents may prevent inhospital deaths. Furthermore, same-admission CABG rates have decreased dramatically, an association seen with the introduction of stenting, but not with volume shifts.


Revealing Phase Transition in Ni-Rich Cathodes via a Nondestructive Entropymetry Method.
With the expanding requirements of recent energy regulations and economic interest in high-performance batteries, the need to improve battery energy density and safety has gained prominence. High-energy-density lithium batteries, employed in next-generation energy storage devices, rely on nickel-rich cathode materials. Since they have extremely high charge/discharge capacity, high operating voltage, prolonged cycle life, and lower cost, nickel-rich cathode materials such as Ni-rich NCM (LiNix > 0.8CoyMnzO2) and Ni-rich NCA (LiNix > 0.8CoyAlzO2) are of particular interest to researchers. Several in situ characterization methodologies are currently used to understand lithium-ion battery electrode response and deterioration better. Nevertheless, in many contexts, these measurement methodologies must be combined with specially designed cells and electrode materials with distinct forms, which is sometimes inconvenient. As an alternative, thermo-voltammetric dynamic characterization may be utilized to describe the thermal internal characteristics of various electrode materials, such as the structural changes and electrode reactions that occur during charging and discharging. In this paper, a nondestructive entropy measurement method demonstrates that phase change occurs for NCM (LiNi0.83Co0.12Mn0.05O2) and NCA (LiNi0.88Co0.09Al0.03O2) at 40-30% of state of charge (SOC) and 90-80% of SOC, respectively. This is confirmed by ex situ X-ray diffraction (XRD) measurements for these highly popular cathodes.


Reproductive toxicity tests: retrospect and prospect.
1. The design of the classical three segment reproductive test for new drugs is described and the relative merits of the USA/EEC and the Japanese guidelines are discussed. 2. The importance of pharmacokinetic studies in the interpretation of teratology studies and extrapolation to humans is mentioned in relation to caffeine, sodium valproate and cyclophosphamide. 3. Changing ideas on the design of multi-generation studies are reviewed. 4. Recent developments in the fields of behavioural teratology, chemicals in breast milk and transplacental carcinogenesis are described.


[The effect of a single dose of 50 micrograms of salmeterol (Serevent, Glaxo) on pulmonary functional parameters].
The study aimed at estimating the acting duration of salmeterol (Serevent, Glaxo), a long-term beta 2-agonist bronchodilator, when given in a single dose (50 micrograms). Two flow rates (FEV1, MEF50) the overall airways resistance to flow (Raw), and intrathoracic gas volume (ITGV) were measured at 15 minutes, then every two hours, up to 12 hours after salmeterol administration, in 8 asthma patients with ample reversible obstructive ventilation disfunction. Lung function parameters were quickly improved, and remained at higher values than the initial ones even at 12 hours after drug administration, the bronchodilating effect being of a similar amplitude for Raw, ITGV and MEF50, which suggests a favorable answer both in the whole bronchial tree and the peripheral airways segment.


Radiographic analysis of transforaminal lumbar interbody fusion for the treatment of adult isthmic spondylolisthesis.
The radiographs of 35 consecutive adult patients with isthmic spondylolisthesis who underwent a transforaminal lumbar interbody fusion (TLIF) with one or two Brantigan carbon fiber cages and pedicle screw instrumentation were evaluated. Anterolisthesis, disk space height, and slip angle were measured in preoperative and postoperative standing neutral radiographs. Anterolisthesis was reduced and disk space height was increased with the TLIF procedure. Average slip angle, however, was not significantly altered. The restoration of lordosis across the listhetic disk space correlated with a more anterior placement of the interbody cage within the disk space. The TLIF technique, performed with the Brantigan cage and pedicle screw instrumentation, appears to be able to restore disk height and reduce forward translation in patients with isthmic spondylolisthesis, but improvement in sagittal alignment is dependent upon anterior placement of the interbody device.


Respiratory disease in agricultural workers: mortality and morbidity statistics.
To quantify the respiratory disease burden among agricultural workers, we examined the 1988-1998 National Center for Health Statistics (NCHS) "Multiple Cause of Death Data" and the 1988-1994 Third National Health and Nutrition Examination Survey data (NHANES III). Proportionate mortality ratios (PMRs) were determined for 11 respiratory conditions among 6 agricultural groups: crop farm workers, livestock farm workers, farm managers, landscape and horticultural workers, forestry workers, and fishery workers. Prevalence ratios (PRs) were determined for 12 respiratory conditions among 3 agricultural groups: farm workers, farm managers, and other agricultural workers. Disease categories groups were based on the 9th International Classification of Diseases and the agricultural groups on the NCHS or NHANES III industry and occupation codes, respectively. Crop farm workers and livestock farm workers had significantly elevated mortality for several respiratory conditions, with mortality for hypersensitivity pneumonitis being 10 and 50 times higher than expected. Landscape and horticultural workers had significantly elevated mortality for abscess of the lung and mediastinum and chronic airways obstruction. Forestry workers had significantly elevated mortality for pulmonary tuberculosis, chronic airways obstruction, and pneumonia. Prevalence of wheeze was elevated for female farm workers, shortness of breath was elevated for farm workers who had ever smoked, and hay fever was elevated for black, non-Hispanic farm workers. Prevalence of asthma was elevated for other agricultural workers who had ever smoked. Farm workers had a PR of 173 for obstructive respiratory abnormality. Continued improvement in occupational health surveillance systems for agriculture is essential to help guide prevention efforts for respiratory disease.


[Ethics committees bear a responsibility for patient information. Informed consent implies that the patient understands what he has consented to].
A cornerstone in health care is the duty to inform patients not only of their right to partake in decisions about their care but also of the various options for treatment. This applies particularly in clinical research, for which the Helsinki Declaration has defined patients' rights. Informed consent is of great importance both in routine care and in clinical research. Directives defining informed consent in relation to clinical trials have been issued by The EU Commission. The Department of Health and Social Security in England has also published several documents governing patient consent. Even if information is given to the patient it is not always comprehended. In one study of cancer treatment about one third of the patients had misunderstood the information in certain respects.


Molecular quantification of Saccharomyces cerevisiae α-pheromone secretion.
Saccharomyces cerevisiae yeast cells court each other by producing an attractive sex pheromone specific to their mating type. Cells detect the sex pheromone from potential mates using a well-defined intracellular signalling cascade that has become a model for studying signal transduction. In contrast, the factors contributing to the production of pheromone itself are poorly characterized, despite the widespread use of the S. cerevisiae α-pheromone secretion pathway in industrial fungal protein expression systems. Progress in understanding pheromone secretion has been hindered by a lack of a precise and quantitative pheromone production assay. Here, we present an ELISA-based method for the quantification of α-pheromone secretion. In the absence of pheromone from the opposite mating type, we found that each cell secretes over 550 mature α-pheromone peptides per second; 90% of this total was produced from MF α1. The addition of a-pheromone more than doubled total α-pheromone secretion. This technique offers several improvements on current methods for measuring α-pheromone production and will allow detailed investigation of the factors regulating pheromone production in yeast.


Factors contributing to outcome following traumatic brain injury.
Traumatic brain injury results in some distinctive patterns of cognitive, behavioural and physical impairment which impact significantly on independent living skills and participation in work or study, social and leisure activities and interpersonal relationships. There is, however, still considerable variability in outcome across individuals in each of the reported domains. This has led to a significant body of research examining factors associated with outcome. A range of injury-related, personal and social factors have been shown to influence survival, as well as cognitive, functional and employment outcome. This paper reviews the factors associated with each of these aspects of outcome specifically injury-related factors, including neuroimaging findings, GCS and PTA, other injuries, and cognitive and behavioural impairments; demographic factors, including age, gender, genetic status, education, pre-injury IQ and employment status; and social factors including family and other social support, cultural factors, pre-injury psychiatric history and coping style. The paper identifies contributions and complex interrelationships of all of these factors to outcome following TBI. It concludes with a brief discussion of the implications of these factors for the rehabilitation process.


A Case of Functional Bowel Disease Misdiagnosed as Carcinoid Syndrome.
An elevated urinary 5-hydroxyindoleacetic acid (U5-HIAA) is typically thought of to be related to carcinoid syndrome. It is widely known that several other etiologies can cause high levels; however, those etiologies typically cause mild elevations. We present a unique situation of a highly elevated U5-HIAA not because of a neuroendocrine tumor. Gastroenterologists need to have an approach in mind if they encounter this predicament. We aim to raise awareness of this situation to emphasize the importance of a thorough medication history and avoid unnecessary testing.


Splenic arteriovenous fistula with infarcted spleen.
A 25-year-old woman developed epigastralgia and abdominal bruit in the left hypochondrium. Radiologic investigation included Doppler ultrasonography, angiography and computed tomography and revealed splenic artery aneurysm and arteriovenous fistula resulting in an almost totally infarcted spleen.


Developmental Biology: Hox Timing Determines Limb Placement.
Hox genes are known to determine vertebral identity along with being required for normal limb patterning. A new study now finds that differential expression timing of Hox genes in the lateral plate mesoderm determines limb placement as well.


Parameter estimation in a coupled system of nonlinear size-structured populations.
A least squares technique is developed for identifying unknown parameters in a coupled system of nonlinear size-structured populations. Convergence results for the parameter estimation technique are established. Ample numerical simulations and statistical evidence are provided to demonstrate the feasibility of this approach.


Reticulate Evolution of the Rock Lizards: Meiotic Chromosome Dynamics and Spermatogenesis in Diploid and Triploid Males of the Genus Darevskia.
Knowing whether triploid hybrids resulting from natural hybridization of parthenogenetic and bisexual species are fertile is crucial for understanding the mechanisms of reticulate evolution in rock lizards. Here, using males of the bisexual diploid rock lizard species Darevskia raddei nairensis and Darevskia valentini and a triploid hybrid male Darevskia unisexualis × Darevskia valentini, we performed karyotyping and comparative immunocytochemistry of chromosome synapsis and investigated the distribution of RAD51 and MLH1 foci in spread spermatocyte nuclei in meiotic prophase I. Three chromosome sets were found to occur in cell nuclei in the D. unisexualis × D. valentini hybrid, two originating from a parthenogenetic D. unisexualis female and one from the D. valentini male. Despite this distorted chromosome synapsis and incomplete double-strand breaks repair in meiotic prophase I, the number of mismatch repair foci in the triploid hybrid was enough to pass through both meiotic divisions. The defects in synapsis and repair did not arrest meiosis or spermatogenesis. Numerous abnormal mature spermatids were observed in the testes of the studied hybrid.


Modeling of polychlorinated biphenyl removal from contaminated soil using steam.
Microwave-generated steam technology shows promise as an effective remediation alternative for removal of polychlorinated biphenyls (PCBs) from contaminated soils, based on our laboratory-scale experiments. The overall process can be described by a nonisothermal, unsteady, coupled heat and multicomponent PCB mass-transport model in a multiphase, variably saturated, porous soil medium. In this paper, a multicomponent PCB mass-transport model is presented that assumes evaporation is an important removal mechanism and that is based on first-order mass transfer between the interface of PCB films and the bulk steam. The model was calibrated using the experimental data, and the calibrated model was verified by computational mass-balance checks and comparisons with laboratory-scale column experimental results. From a qualitative point of view, the calibrated model successfully simulated the transport of PCBs in variably saturated soil media. The calculated increase/decrease factors of physicochemical properties of PCBs as a function of temperature in the soil, water, and free phases were consistent with the model hypothesis of an evaporation process. The effects of mass-transfer coefficients and initial PCB concentrations in the soils on PCB removal rates were investigated using the numerical code. It was determined that the PCB removal rates were sensitive to mass-transfer coefficients and initial PCB concentrations. Although the steam:soil mass ratios required to achieve a given percentage removal were lower for lower initial PCB soil concentrations, steam: soil mass ratios required to achieve a given unit mass removal were higherfor lower initial PCB soil concentrations.


Glutamate dehydrogenase isoenzymes in the bovine retina and human leukocyte.
In the present study, we investigated the enzymatical properties of the heat-labile and heat-stable glutamate dehydrogenases (GDHs) from the bovine retina and human leukocytes. Retinal GDHs were mitochondrial enzymes with an optimal pH of 7.5. Heat-labile (membrane-associated form) and heat-stable (soluble form) GDHs were found in the bovine retina as well as in the human leukocytes. At least 5 GDH isoenzymes were found in the retina and leukocytes by nondenaturing polyacrylamide gel electrophoresis. After heat treatment, the high-speed pellet obtained from centrifugation of the human leukocytes at 100,000 x g retained the 3 smaller isoenzymes but had lost the 2 larger isoenzymes. Both heat-labile and heat-stable GDH were found in the neuroretina, retinal pigment epithelium and optic nerve with high activities. Our results suggest that these tissues may be the main active sites of the GDH deficiency.


Estrogen receptor α (ERα)-binding super-enhancers drive key mediators that control uterine estrogen responses in mice.
Estrogen receptor α (ERα) modulates gene expression by interacting with chromatin regions that are frequently distal from the promoters of estrogen-regulated genes. Active chromatin-enriched "super-enhancer" (SE) regions, mainly observed in in vitro culture systems, often control production of key cell type-determining transcription factors. Here, we defined super-enhancers that bind to ERα in vivo within hormone-responsive uterine tissue in mice. We found that SEs are already formed prior to estrogen exposure at the onset of puberty. The genes at SEs encoded critical developmental factors, including retinoic acid receptor α (RARA) and homeobox D (HOXD). Using high-throughput chromosome conformation capture (Hi-C) along with DNA sequence analysis, we demonstrate that most SEs are located at a chromatin loop end and that most uterine genes in loop ends associated with these SEs are regulated by estrogen. Although the SEs were formed before puberty, SE-associated genes acquired optimal ERα-dependent expression after reproductive maturity, indicating that pubertal processes that occur after SE assembly and ERα binding are needed for gene responses. Genes associated with these SEs affected key estrogen-mediated uterine functions, including transforming growth factor β (TGFβ) and LIF interleukin-6 family cytokine (LIF) signaling pathways. To the best of our knowledge, this is the first identification of SE interactions that underlie hormonal regulation of genes in uterine tissue and optimal development of estrogen responses in this tissue.


Visuospatial memory and learning in first-episode schizophreniform psychosis and established schizophrenia: a functional correlate of hippocampal pathology?
Despite a number of studies that have indicated impaired memory function in patients with schizophrenia, there have been few that have used a sensitive measure of right medial temporal lobe pathology. Given the reported findings of reduced hippocampal volume in schizophrenia, we used a theoretically sensitive test of the right medial temporal lobe to determine the nature of the visuospatial memory deficit in the disorder. Seventy-six patients (37 with a first-episode schizophreniform psychosis, and 39 with established schizophrenia) were compared with 41 comparison subjects on a number of tests of visuospatial memory. These included spatial working memory, spatial and pattern recognition memory and a pattern-location associative learning test. Both patient groups displayed recognition memory deficits when compared to the comparison group. However, only those patients with established schizophrenia (of 9 years duration on average) were impaired on the associative learning test. The results indicate either a progressive decline in visuospatial associative learning ability over the course of the disorder, or that poor visuospatial associative learning is a marker for poor prognosis. In addition, these results have implications for our understanding of the role of the right medial temporal lobe in the pathophysiology of schizophrenia.


Endocrine responses to exogenous bombesin and gastrin releasing peptide in conscious calves.
The effects of I.V. infusions of synthetic amphibian bombesin and porcine gastrin releasing peptide (GRP), at a dose of 5 pmol/kg. min for 30 min, have been investigated in conscious calves 3-6 weeks after birth. The protocols produced a closely similar rise in the bombesin-like immuno-reactivity of the arterial plasma of 208 +/- 14 pmol/l (bombesin) and 210 +/- 32 pmol/l (GRP) which fell exponentially with a half-life of about 3 min when the infusions were terminated. Neither peptide produced a discernible change in mean heart rate or aortic blood pressure, or in the mean arterial plasma concentrations of enteroglucagon, gastric inhibitory peptide (GIP), gastrin or cholecystokinin (CCK). GRP, but not bombesin, produced a small but significant rise in the mean plasma somatostatin concentration. Both peptides produced a significant rise in mean plasma pancreatic glucagon and pancreatic polypeptide concentration and proved to be exceptionally potent insulinotropic agents. These responses were associated with a rise in plasma glucose concentration which could not be attributed to a direct action of GRP on the liver. The distribution of bombesin-like immunoreactivity in the gastrointestinal tract was consistent with the findings of other workers who have concluded that it is restricted to nerve terminals. However, our other findings show that GRP is capable of acting as a true hormone.


Machine-learning based brain age estimation in major depression showing no evidence of accelerated aging.
Molecular biological findings indicate that affective disorders are associated with processes akin to accelerated aging of the brain. The use of the BrainAGE (brain age estimation gap) framework allows machine-learning based detection of a gap between age estimated from high-resolution MRI scans an chronological age, and thus an indicator of systems-level accelerated aging. We analysed 3T high-resolution structural MRI scans in 38 major depression patients (without co-morbid axis I or II disorders) and 40 healthy controls using the BrainAGE method to test the hypothesis of accelerated aging in (non-psychotic) major depression. We found no significant difference (or trend) for elevated BrainAGE in this pilot sample. Unlike previous findings in schizophrenia (and partially bipolar disorder), unipolar depression per se does not seem to be associated with accelerated aging patterns across the brain. However, given the limitations of the sample, further study is needed to test for effects in subgroups with comorbidities, as well as longitudinal designs.


Bacterial endotoxins in umbilical cord blood of neonates.
We tested umbilical cord blood from 255 infants for evidence of bacterial endotoxins. Using a Limulus lysate gelation technique, endotoxin-like activity (ELA) was detected in 13 (9.1%) of 142 term infants and in 23 (20.3%) of 113 preterm infants (p less than 0.05), in concentrations ranging from 30 to 3,000 pg Escherichia coli equivalent activity per milliliter of plasma. No factors predisposing to endotoxemia could be detected in term pregnancies but among ELA+ premature infants, placental cultures more frequently revealed gram-negative species (p less than 0.05). Cord blood endotoxemia in the concentrations observed was without obvious consequence in mothers and term infants. Our data confirm the existence of natal endotoxemia, a potential mechanism of perinatal injury.


[Therapy of advanced amoeba keratitis with keratoplasty à chaud and adjuvant cryotherapy].
Since the mid-1980s acanthamoeba keratitis has been diagnosed with increasing frequency, especially in contact lens wearers. The assignment to specialized centers is often delayed many months and there is hardly any chance of controlling the disease by conservative treatment alone. In these cases, penetrating keratoplasty offers the only chance for rehabilitation. The therapeutic role of penetrating keratoplasty and supportive intraoperative cryotherapy is demonstrated by the courses of six patients with unilateral acanthamoeba keratitis. The data of six patients aged 41.2 (22-63) years with medically uncontrollable acanthamoeba keratitis were evaluated retrospectively. The diagnosis was confirmed histologically in all cases. All patients were contact lens wearers. They underwent a total of ten keratoplasties between November 1986 and January 1995. The donors were 44.8 (23-58) years of age. The transplant diameters varied between 7.7 and 9.5 mm. The margins of the host cornea were intraoperatively frozen by a cryoprobe in three patients with a far advanced stage of corneolimbal parasitic infiltration. During a follow-up period of +/-10.2 (1-22) months, five of six eyes were rehabilitated with visual acuities between 0.4 and 1.0. One eye went blind after the fourth keratoplasty because of uncontrollable secondary glaucoma. After three keratoplasties with simultaneous application of cryocoagulation because of an especially high risk of persisting acanthamoeba infection, all corneae remained clear and free of recurrences. In advanced acanthamoeba keratitis which has not responded to conservative treatment, penetrating keratoplasty not only provides elimination of the pathogen, but also good functional results. In far advanced stages, the intraoperative application of cryocoagulation for parasite elimination in the host cornea seems to be a very effective measure against local recurrences of the infection.


Human Stem Cells for Cardiac Disease Modeling and Preclinical and Clinical Applications-Are We on the Road to Success?
Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.


Predictive Modeling of Individual Human Cognition: Upper Bounds and a New Perspective on Performance.
Model evaluation is commonly performed by relying on aggregated data as well as relative metrics for model comparison and selection. In light of recent criticism about the prevailing perspectives on cognitive modeling, we investigate models for human syllogistic reasoning in terms of predictive accuracy on individual responses. By contrasting cognitive models with statistical baselines such as random guessing or the most frequently selected response option as well as data-driven neural networks, we obtain information about the progress cognitive modeling could achieve for syllogistic reasoning to date, its remaining potential, and upper bounds of performance future models should strive to exceed. The methods presented in this article are not restricted to the domains of reasoning but generalize to other fields of behavioral research and can serve as useful additions to the modern modeler's toolbox.


Structured emulsions as butter substitutes: effects on physicochemical and sensory attributes of shortbread cookies.
Reformulation of foods products to reduce total and saturated fats while maintaining acceptable structure, texture and mouthfeel poses an important challenge to the food industry. In this work, the use of structured emulsions (fibre-induced oil-in-water biphasic systems with reduced total and saturated fats) is proposed to replace butter in shortbread cookies. Use of structured emulsions resulted in softer dough that was still workable using a traditional process. Shortbread cookies containing structured emulsions were harder and paler than the butter control but had a significantly reduced saturated fat content. They also received promising scores in the sensory analysis in terms of texture and overall acceptability, despite the butter product still being the preferred sample. The results of this study indicated that structured emulsions represent a good solution to produce nutritionally improved shortbreads. Optimization of the structured emulsion formulation can provide further improvement of the nutritional, sensory and physicochemical properties of shortbread cookies. © 2018 Society of Chemical Industry.


PRMT6 diminishes HIV-1 Rev binding to and export of viral RNA.
The HIV-1 Rev protein mediates nuclear export of unspliced and partially spliced viral RNA through interaction with the Rev response element (RRE) by means of an arginine rich motif that is similar to the one found in Tat. Since Tat is known to be asymmetrically arginine dimethylated by protein arginine methyltransferase 6 (PRMT6) in its arginine rich motif, we investigated whether the Rev protein could act as a substrate for this enzyme. Here, we report the methylation of Rev due to a single arginine dimethylation in the N-terminal portion of its arginine rich motif and the association of Rev with PRMT6 in vivo. Further analysis demonstrated that the presence of increasing amounts of wild-type PRMT6, as well as a methylation-inactive mutant PRMT6, dramatically down-regulated Rev protein levels in concentration-dependent fashion, which was not dependent on the methyltransferase activity of PRMT6. Quantification of Rev mRNA revealed that attenuation of Rev protein levels was due to a posttranslational event, carried out by a not yet defined activity of PRMT6. However, no relevant protein attenuation was observed in subsequent chloramphenicol acetyltransferase (CAT) expression experiments that screened for RNA export and interaction with the RRE. Binding of the Rev arginine rich motif to the RRE was reduced in the presence of wild-type PRMT6, whereas mutant PRMT6 did not exert this negative effect. In addition, diminished interactions between viral RNA and mutant Rev proteins were observed, due to the introduction of single arginine to lysine substitutions in the Rev arginine rich motif. More importantly, wild-type PRMT6, but not mutant methyltransferase, significantly decreased Rev-mediated viral RNA export from the nucleus to the cytoplasm in a dose-dependent manner. These findings indicate that PRMT6 severely impairs the function of HIV-1 Rev.


Four stages of hepatic hematopoiesis in human embryos and fetuses.
The liver is a major hematopoietic organ during embryonic and fetal development in humans. Its hematopoietic activity starts during the first weeks of gestation and continues until birth. During this period the liver is colonized by undifferentiated hematopoietic stem cells (HSCs) that gradually differentiate and once mature, enter the circulatory system through the hepatic sinusoids, this process is called hepatic hematopoiesis. The morphology of hepatic hematopoiesis, has been studied in humans through the years, and led to a characterization of all the cell types that make up these phenomena. Studies on murine models also helped to describe the extent of hepatic hematopoiesis at different gestational ages. Using this knowledge, we attempted to describe how hepatic hematopoiesis morphologically evolves as gestation progresses, in human embryos and fetuses. Thus, we observed a total of 32 tissue specimens obtained from the livers of embryos and fetuses at different gestational ages. Basing our observations on the four stages of liver hematopoiesis identified by Sasaki and Sonoda in mice, we also described four consecutive stages of liver hematopoiesis in humans, which resulted to be highly similar to those described in murine models.


Extravascular natural cytotoxicity in man: Anti-K562 activity of lymph-node and tumour-infiltrating lymphocytes.
A major distinction is reported between the cytolytic activity of peripheral blood lymphocytes (PBL) and that of lymph-node and tumour-infiltrating lymphocytes (TIL) against targets of the NK-sensitive K562 cell line in short-term 51Cr release assays. In the PBL of normal donors and lung cancer patients in whom disease was advanced anti-K562 reactivity, though variable, was consistently detectable and this activity could be augmented to a similar extent in patients and controls by treatment of effectors with exogenous interferon (IF). By contrast anti-K562 activity in lymph-node cells (LNC) and TIL was virtually absent and significant levels could not be induced by exposure to IF. This activity was not attributable to coexistent suppressor cells for NK function since admixture of LNC and TIL with normal PBL failed to modulate K562 killing by the latter. The results imply that K562-reactive NK cells and their precursors may frequently be present at sub-threshold levels in the lymph nodes of tumour-bearing patients and a similar explanation could account for the inactivity of TIL. However, in the latter situation, actively-induced NK dysfunction in situ incapable of regeneration by IF, and attributable to as yet undefined tumour-associated factors, may also be involved.


Demographic differences in the cascade of care for unhealthy alcohol use: A cross-sectional analysis of data from the 2015-2019 National Survey on Drug Use and Health.
The screening, brief intervention, and referral to treatment (SBIRT) model is recommended by the U.S. Preventive Services Task Force to improve recognition of and intervention for unhealthy alcohol use. How SBIRT implementation differs by demographic characteristics is poorly understood. We analyzed data from the 2015-2019 National Survey on Drug Use and Health from respondents ≥18 years old who used an outpatient clinic and had at least one alcoholic drink within the past year. Respondents were grouped into one of three mutually exclusive groups: "no binge drinking or alcohol use disorder (AUD)," "binge drinking without AUD," or "AUD." Outcome variables were likelihood of screening, brief intervention (BI), referral to treatment (RT), and AUD treatment. The demographic predictors on which outcomes were regressed included gender, age, race and ethnicity, sexual orientation, insurance status, and history of military involvement. Consistent with SBIRT guidelines, the entire sample was included in the screening model; screened persons with either binge drinking without AUD or with AUD were included in the BI model; screened persons with AUD were included in the RT model, and persons referred to treatment with AUD were included in the AUD treatment model. Analyses included 120,804 respondents. Women were more likely than men to be screened, but less likely to receive BI or RT. When referred to treatment, women were more likely than men to receive it. Persons aged ≥50 were least likely to be screened about alcohol, but most likely to receive BI, while persons aged 18-25 were least likely to receive BI or AUD treatment. Racial and ethnic minorities were less likely than White persons to be screened; Asians were less likely to receive RT, and Black persons were less likely to receive treatment than White persons. Persons identifying as gay, lesbian, or bisexual were equally as likely or more likely to receive SBIRT or AUD treatment as those identifying as heterosexual. Persons without insurance were less likely to be screened than those with insurance. Persons with a history of military involvement were more likely to be screened and receive BI and RT than persons who had not served in the military. Demographic disparities in SBIRT implementation exist. Addressing the sources of these disparities and minimizing attrition from care could improve outcomes for persons with unhealthy alcohol use.


Reality check of laboratory service effectiveness during pandemic (H1N1) 2009, Victoria, Australia.
In Australia, the outbreak of pandemic (H1N1) 2009 began in Melbourne, Victoria; in the first 17 days, the Victorian Infectious Diseases Reference Laboratory detected 977 cases. Although the laboratory had a pandemic plan in place, a retrospective evaluation found 3 major variations from plan assumptions: 1) higher peak demand not limited by a case definition, 2) prolonged peak demand because containment attempts continued despite widespread influenza, and 3) unexpected influence of negative test results on public health actions. Although implementation of the plan was generally successful, the greatest challenges were limited availability of skilled staff and test reagents. Despite peak demand of 1,401 tests per day, results were provided within the usual 24 hours of specimen receipt; however, turnaround time seemed slower because of slow transport times (>3 days for 45% of specimens). Hence, effective laboratory capability might be enhanced by speeding transport of specimens and improving transmission of clinical data.


Complications of chronic suppurative otitis media: challenge for a developing country.
This study aims to investigate the frequency and management of complications of chronic suppurative otitis media (CSOM). Out of 376 patients with CSOM, 44 patients (25 males, 19 females; mean age 48.5±3.5 years; range 21 to 76 years) meeting study criteria were enrolled in this descriptive cross sectional study which was conducted at the Department of Ear Nose and Throat, Head and Neck Surgery, Postgraduate Medical Institute, Lady Reading Hospital Peshawar. All newly diagnosed patients having CSOM with complications were enrolled. The complications were treated first. Intracranial abscesses were evacuated by neurosurgeons. Radical and modified radical mastoidectomy were performed. Majority of the patients presented in the second and third decade of life (21-30 years: 27.27%, 31-40 years: 18.18%). Most of the patients (59.1%) had lower socioeconomic status. Canal wall down mastoidectomy was the most common (79.5%) procedure performed. Cholesteatoma was the most common operative finding (100%). Among extracranial complications, subperiosteal abscess was the most common finding (38.63%), while extradural abscess outnumbered (22.72%) in intracranial complications. Complications of CSOM commonly affect younger people with low socioeconomic status. Collaborating with neurosurgeons may assist in the successful management of this infection.


An assessment of seed quality and its influence on productivity estimation in an industrial antibiotic fermentation.
This study investigates the benefits of including seed quality information into data-based models for final productivity estimation in an industrial antibiotic fermentation process. Multiway principal component analysis is applied to assess the seed quality using routinely gathered plant data. Multiway partial least-squares regression is then used to estimate the final productivity using data from the main fermentation only. The issue of selecting appropriate process variables as inputs is investigated. Subsequently, seed characteristics are included into the estimation models to assess the benefits of including information from this stage for productivity estimation. It is shown that it is possible to extract seed fermentation features related to the final productivity both at pilot and production scales. It is postulated that significant influential variations are mirrored in monitored variables during the main fermentation, and therefore seed quality is implicitly accounted for.


Downregulating forkhead box M1 inhibits proliferation by inhibiting autophagy in the sw480 cell line.
Forkhead Box M1 (FoxM1) is one of the most important oncogenes, and overexpression of FoxM1 has been reported in many cancers, including colon cancer. In the present study, the authors attempted to reveal the mechanism underlying its effects on proliferation through autophagy in the sw480 cell line. FoxM1 is knocked down through short hairpin (sh)RNA in the sw480 cell line. A series of experiments were conducted to examine it function on proliferation and LC3 and P62 were used to measure level of autophagy. Autophagy in the shFoxM1 cell was demonstrated as significantly inhibited compared with the negative control. Additional auto-fluex was also tested, downregulation of FoxM1 served the same role as BA1 in autophagy. Furthermore, downregulating FoxM1 inhibited cell proliferation in the sw480 cell line.


TP53 codon 72 polymorphism and colorectal cancer susceptibility: a meta-analysis.
Colorectal cancer constitutes a significant proportion of the global burden of cancer morbidity and mortality. A number of studies have been conducted to explore whether TP53 codon 72 polymorphism is associated with colorectal cancer susceptibility. However, controversial results were obtained. In order to derive a more precise estimation of the relationship, we systematically searched Medline, Google scholar, and Ovid database for studies reported before May 2010. A total of 3603 colorectal cancer cases and 5524 controls were included. TP53 codon 72 polymorphism was not associated with colorectal cancer risk in all genetic models (for dominant model: OR = 0.99, 95% CI: 0.86-1.15; for recessive model: OR = 1.00, 95% CI: 0.81-1.23; for Arg/Pro vs. Arg/Arg: OR = 1.00, 95% CI: 0.87-1.15; for Pro/Pro vs. Arg/Arg: OR = 0.97, 95% CI: 0.76-1.25). In the subgroup analyses by ethnic groups and sources of controls, no significant associations were found in all models. Taken together, this meta-analysis suggested that the biologically usefulness of TP53 codon 72 polymorphism as a selection marker in colorectal cancer susceptibility may be very limited.


Predictors of parental satisfaction with the pediatric ophthalmology care in a Brazilian hospital.
The purpose of this cross-sectional study was to assess the satisfaction of parents of visually impaired children with the pediatric ophthalmology care in a Brazilian hospital and to associate parental satisfaction with predictor variables. The study enrolled children with a binocular and monocular visual impairment aged between 4 and 17 years from a single site in Brazil between June 2019 and May 2020. Parents or legal guardians answered the Brazilian version of the Pediatric Quality of Life InventoryTM (PedsQLTM 3.0) Healthcare Satisfaction Generic - Parents. Linear regression analysis was used to investigate the association between the PedsQL scores and predictor variables. The sample included 82 children and their respective parents. The mean PedsQL score was 90.3 ± 6.6 (out of 100). In the univariate model, child female sex (p = 0.056), child older age (p = 0.078), better eye visual acuity (VA; p = 0.016), and worse eye VA (p = 0.008) were significantly associated with higher scores. The multivariate estimates identified the worse eye VA (p = 0.034) as a predictor of parental satisfaction. In summary, parents' satisfaction with this pediatric ophthalmology care was high. Nevertheless, a continuous evaluation is warranted to keep up with parents' expectations and plan for possible improvements in clinical practice.


Should deciduous teeth be restored? Reflections of a cariologist.
Whether deciduous teeth should be restored has caused controversy for at least 150 years and the argument rages on. Dental caries is a controllable process. The role of operative dentistry and restorations, as far as caries control is concerned, is to make cavitated, uncleansible lesions accessible to plaque control. However, deciduous teeth are exfoliated and perhaps non-operative treatments (plaque control, fluoride, diet) are all that are required to take cavitated teeth pain-free to exfoliation. Are such techniques child-friendly, obviating the need for anaesthesia or the use of handpieces? Alternatively, are they wanton neglect? This paper is written by a cariologist who never treated children, to present alternative managements and rehearse these arguments from a cariological perspective. This paper might serve as a discussion document for a group of dentists deciding practice policy with regard to the management of caries in deciduous teeth.


A high-capacity model for one shot association learning in the brain.
We present a high-capacity model for one-shot association learning (hetero-associative memory) in sparse networks. We assume that basic patterns are pre-learned in networks and associations between two patterns are presented only once and have to be learned immediately. The model is a combination of an Amit-Fusi like network sparsely connected to a Willshaw type network. The learning procedure is palimpsest and comes from earlier work on one-shot pattern learning. However, in our setup we can enhance the capacity of the network by iterative retrieval. This yields a model for sparse brain-like networks in which populations of a few thousand neurons are capable of learning hundreds of associations even if they are presented only once. The analysis of the model is based on a novel result by Janson et al. on bootstrap percolation in random graphs.


Flying solo: a single year-single surgeon community hospital replantation/ revascularization experience.
A recent 12-month review of the emergent replantation/revascularization experience of a solo practice microsurgeon in a community hospital environment is presented. A total of 67 digits and/or hands/limbs were operated on in 51 patients with a success rate of 87 percent. There were nine failures, all in digits with crush-avulsion etiologies. These results support the position that the single microsurgeon practicing in a community hospital environment can provide levels of care for patients with amputated or devascularized digits and parts comparable to tertiary medical centers.


Study of Elastin, Hydrolyzed Collagen and Collagen-like Products in a Tri-Layered Chitosan Membrane to Test Anti-Aging Skin Properties.
The use of animal testing in the cosmetic industry is already prohibited in more than 40 countries, including those of the EU. The pressure for it to be banned worldwide in the future is increasing, so the need for animal alternatives is of great interest today. In addition, using animals and humans in scientific research is ethically reprehensible. This study aimed to prove some of the anti-aging properties of elastin (EL), hydrolyzed collagen (HC), and two vegan collagen-like products (Veg Col) in a tri-layered chitosan membrane that was ionically crosslinked with sodium tripolyphosphate (TPP). In the first approach, as a way of representing different layers of a biological system, such as the epidermis and the two dermis sublayers, EL, HC, or Veg Col were independently introduced into the two inner layers (2L(i+b)). Their effects were compared with those of their introduction into three layers (3L). Different experiments were performed on the membrane to test its elasticity, hydration, moisture retention, and pore reduction at different concentrations of EL, HC, and Veg Col, and the results were normalized vs. a blank membrane. This new alternative to animal or human testing can be suitable for proving certain efficacy claims for active ingredients or products in the pharmaceutical, nutritional, and cosmetic fields.


Risk of developing tuberculosis under anti-TNF treatment despite latent infection screening.
In patients treated with TNF-antagonists, incident cases of tuberculosis (TB) after a negative screening have been reported, leading to the suggestion that improved TB testing is necessary. The aim of the current study is to establish the incidence of TB and its characteristics in patients with inflammatory bowel disease (IBD) under TNF antagonists to design improved prevention strategies. IBD patients from a single center treated with anti-TNF therapy between January 2000 and September 2011 were identified through a database that prospectively records clinical data, treatments and adverse events. During the study period 423 patients received anti-TNF therapy. Screening for latent TB infection (LTBI) previous to anti-TNF treatment was positive in 30 patients (6.96%). Seven patients (1.65%) developed TB while under anti-TNF treatment. Six patients (five under immunosuppressant treatment) had a negative LTBI screening. TST was positive in one patient not receiving immunosuppressants, and was treated with isoniazid before starting anti-TNF therapy. In 4 patients TB was diagnosed within the first 16 weeks after starting anti-TNF therapy. Three cases had pulmonary TB and 4 extrapulmonary disease. In the IBD population under study, incidence of TB infection associated with anti-TNF therapy is higher than that reported in controlled trials and occurs early after treatment initiation. False negative results of LTBI despite appropriate measures may occur, suggesting that more effective screening strategies are needed.


Detection of Staphylococcus aureus with biotinylated monoclonal antibodies directed against staphylococcal TNase complexed to avidin-peroxidase in a rapid sandwich enzyme-linked immunofiltration assay (sELIFA).
For rapid identification of Staphylococcus aureus, a monoclonal antibody (MAb)-biotin-avidin-peroxidase complex, directed against the S. aureus thermostable nuclease (TNase), was formed and used in a rapid three-step sandwich enzyme-linked immunofiltration assay (sELIFA) and a three-step sandwich enzyme-linked immunosorbent assay (sELISA). The MAb-peroxidase complex was formed by incubating the biotinylated MAbs with a streptavidin-peroxidase conjugate and the complex was purified by gel permeation chromatography. When compared with a four-step MAb-based sELISA described previously, this complex permitted one reagent step to be omitted in a three-step sELISA, and the test time was significantly reduced. The test sensitivity was slightly reduced in the three-step ELISA (detection limit 1.0-2.0 ng of TNase/ml) when compared to the four-step sELISA (detection limit 0.5-1.0 ng of TNase/ml). The sELIFA method was based on the filtration of bacterial culture supernates through nitrocellulose membrane disks pre-spotted with a MAb directed against the S. aureus TNase, followed by detection with the MAb-peroxidase complex (three-step sELIFA). A detection limit of 0.5-2.0 ng of TNase/ml was achieved with the three-step sELIFA, depending on the filtrate volume of culture supernates. The total test time was 10-15 min when pre-spotted and blocked membranes were used. A total of 85 bacterial strains was tested in the sELIFA. All the 28 S. aureus strains showed positive results, but none of the 57 non-S. aureus strains did so, although some of these produced thermostable nuclease activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Regional ventilation redistribution measured by electrical impedance tomography during spontaneous breathing trial with automatic tube compensation.
Automatic tube compensation (ATC) was developed to overcome the flow resistance of endotracheal tube and decrease the imposed work of breathing. Although ATC is used as an evidence-based strategy to predict successful weaning from assisted ventilation, the changes in regional ventilation distribution induced by this technique are not known. We hypothesized that continuous positive airway pressure plus ATC (CPAP + 100%ATC) could reactivate the respiratory muscles in patients with prolonged mechanical ventilation (PMV) more effectively than volume assist-control mandatory ventilation (ACMV). A total of 16 PMV patients were included. Patients were ventilated under volume ACMV mode and subsequently under CPAP + 100%ATC for 50 min. Two periods of 5 min electrical impedance tomography (EIT) data at the end of each mode were analyzed. Tidal variations of electrical impedance determined by EIT during CPAP + 100%ATC were significantly smaller than during ACMV (p < 0.001), while no significant differences in end-expiratory lung impedance were found. Regional ventilation was distributed significantly more towards dorsal regions during CPAP + 100%ATC as indicated by the EIT-based index center of ventilation (46.2 ± 5.8 during ACMV versus 51.7 ± 6.5 during CPAP + 100%ATC, values in %, p < 0.001). However, the overall degree of ventilation inhomogeneity was not improved as indicated by the global inhomogeneity index (0.42 ± 0.09 during ACMV versus 0.42 ± 0.06 during CPAP + 100%ATC). The onset of ventilation was significantly less delayed during CPAP + 100%ATC in both ventral and dorsal regions as indicated by the ventilation delay index (ACMV versus CPAP + 100%ATC, 53.0 versus 42.6 in ventral; 50.2 versus 39.3 in dorsal regions; values in %, p < 0.001). Dorsal redistribution of ventilation and reduction of ventilation delay as identified by EIT indicate that CPAP + 100%ATC was effective in reactivating the respiratory muscles in the PMV patients of the present study.


PINCH-1 is an obligate partner of integrin-linked kinase (ILK) functioning in cell shape modulation, motility, and survival.
PINCH-1 is a widely expressed focal adhesion protein that forms a ternary complex with integrin-linked kinase (ILK) and CH-ILKBP/actopaxin/alpha-parvin (abbreviated as alpha-parvin herein). We have used RNA interference, a powerful approach of reverse genetics, to investigate the functions of PINCH-1 and ILK in human cells. We report here the following. First, PINCH-1 and ILK, but not alpha-parvin, are essential for prompt cell spreading and motility. Second, PINCH-1 and ILK, like alpha-parvin, are crucial for cell survival. Third, PINCH-1 and ILK are required for optimal activating phosphorylation of PKB/Akt, an important signaling intermediate of the survival pathway. Whereas depletion of ILK reduced Ser473 phosphorylation but not Thr308 phosphorylation of PKB/Akt, depletion of PINCH-1 reduced both the Ser473 and Thr308 phosphorylation of PKB/Akt. Fourth, PINCH-1 and ILK function in the survival pathway not only upstream but also downstream (or in parallel) of protein kinase B (PKB)/Akt. Fifth, PINCH-1, ILK and to a less extent alpha-parvin are mutually dependent in maintenance of their protein, but not mRNA, levels. The coordinated down-regulation of PINCH-1, ILK, and alpha-parvin proteins is mediated at least in part by proteasomes. Finally, increased expression of PINCH-2, an ILK-binding protein that is structurally related to PINCH-1, prevented the down-regulation of ILK and alpha-parvin induced by the loss of PINCH-1 but failed to restore the survival signaling or cell shape modulation. These results provide new insights into the functions of PINCH proteins in regulation of ILK and alpha-parvin and control of cell behavior.


Herpes zoster, clinical course and associated diseases: A 5-year retrospective study at Ramathibodi Hospital.
Herpes zoster was more frequently found in immunocompromised hosts and elderly persons than in general population. The aim of this study is to find out the distributions of skin lesions, treatments, complications of herpes zoster and associated diseases that occur in concomitant with or after herpes zoster infections. The medical records of the patients diagnosed as herpes zoster between January 1995 - December 2000 were reviewed. Only the patients who were followed up regularly at Ramathibodi hospital for at least 3 years after the first diagnosis of herpes zoster were enrolled into the study. Demographic data, distribution of skin lesions, treatments, complications of herpes zoster and associated diseases were recorded. Three hundred and ninety-nine cases were enrolled in the study. Three hundred and ninety-eight patients (99.7%) had one dermatomal involvement. Sixty-seven patients (16.8%) had postherpetic neuralgia. Fifty-six patients had associated HIV infection. In 3 years followed up, 17 patients developed HIV infection, 3 patients developed acute leukemia, 2 patients developed mycosis fungoides.


Post-transcriptional regulation of target genes by the sRNA FnrS in Neisseria gonorrhoeae.
Small non-coding RNAs (sRNAs) are well-established post-transcriptional regulators of gene expression in bacteria that respond to a variety of environmental stimuli. They usually act by base-pairing with their target mRNAs, which is commonly facilitated by the RNA chaperone Hfq. In this study we initiated the analysis of the sRNA FnrS of Neisseria gonorrhoeae, which is induced under anaerobic conditions. We identified four putative FnrS target genes using bioinformatics approaches and validated these target genes using translational reporter gene fusions in both Escherichia coli and N. gonorrhoeae, thereby demonstrating their downregulation by direct base-pairing between the respective mRNA and FnrS. We demonstrate deregulation of target mRNAs upon deletion of fnrS and provide evidence that the isc gene cluster required for iron-sulfur cluster biosynthesis, which harbours iscS, which is a direct target of FnrS, is coordinately downregulated by the sRNA. By mutational analysis we show that, surprisingly, three distinct regions of FnrS are employed for interaction with different target genes.


Some changes of the heart bioelectric activity at the cosmonauts under the influence of LBNP in the long duration flights.
There was selected the group of the cosmonauts, who carry out long duration flights on the orbital complex "Mir", in which the tolerance of LBNP test was evaluated as poor (by hemodynamic indices--heart rate, arterial pressure, rheoencephalographic indices). The in-depth analysis of the electrocardiogram (in DS leads) indices was carry oiled on possible disturbances of conductivity and dynamics of temporary or amplitude characteristics. Furthermore is carry oiled the comparative estimation of these indices with the results of ECG analysis at the cosmonauts, who tolerance test good. Studies showed that the most informative ECG indices are the R, T-amplitudes and QT-interval. Under the influence of LBNP, especially during rarefactions on 45 and 50 mm Hg was noted reduction in the R, T-amplitude and the relative extension of QT-interval. The directivity of changes in these indices are identical for the cosmonauts with good and poor tolerance of the test; however in flight manifestation of the changes is more significant for the cosmonauts with poor tolerance of LBNP test. Thus, in the formation of orthostatic stability together with the hemodynamic influences take part the bioelectric processes, which are formed in the myocardium.


Cross-Cultural Validation of the Patient Perception of Integrated Care Survey.
To test the cross-cultural validity of the U.S. Patient Perception of Integrated Care (PPIC) Survey in a Dutch sample using a standardized procedure. Primary data collected from patients of five primary care centers in the south of the Netherlands, through survey research from 2014 to 2015. Cross-sectional data collected from patients who saw multiple health care providers during 6 months preceding data collection. The PPIC survey includes 59 questions that measure patient perceived care integration across providers, settings, and time. Data analysis followed a standardized procedure guiding data preparation, psychometric analysis, and included invariance testing with the U.S. dataset. Latent scale structures of the Dutch and U.S. survey were highly comparable. Factor "Integration with specialist" had lower reliability scores and noninvariance. For the remaining factors, internal consistency and invariance estimates were strong. The standardized cross-cultural validation procedure produced strong support for comparable psychometric characteristics of the Dutch and U.S. surveys. Future research should examine the usability of the proposed procedure for contexts with greater cultural differences.


Potential of BCL2 as a target for chronic lymphocytic leukemia treatment.
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile. Areas covered: This article covers the biology of apoptosis in CLL from a translational viewpoint and deals with the mode of action of BCL2 inhibitors, in particular venetoclax. On this biological rationale, the review then focuses on the results obtained in clinical trials with venetoclax in CLL. Expert commentary: The availability of venetoclax represents a major advance in CLL treatment and offers new opportunities to further improve the results obtained until now by combining venetoclax with other agents. Venetoclax has achieved responses also in patients with TP53 disruption. These results strongly suggest that the mechanism by which venetoclax kills CLL cells might overcome a dysfunctional TP53 that is a major hallmark of chemorefractoriness to conventional antineoplastic agents.


Tunable Lyapunov exponent in inverse magnetic billiards.
The stability properties of the classical trajectories of charged particles are investigated in a two-dimensional inverse magnetic domain, where the magnetic field is zero inside the domain and constant outside. As an example, we present detailed analysis for stadium-shaped domain. In the case of infinite magnetic field, the dynamics of the system is the same as in the Bunimovich billiard, i.e., ergodic and mixing. However, for weaker magnetic fields, the phase space becomes mixed and the chaotic part gradually shrinks. The numerical measurements of the Lyapunov exponent (based on the technique of Jacobi fields) and the regular-to-chaotic phase space volume ratio show that both quantities can smoothly be tuned by varying the external magnetic field. A possible experimental realization of the inverse magnetic billiard is also discussed.


Psoralen Inhibited Apoptosis of Osteoporotic Osteoblasts by Modulating IRE1-ASK1-JNK Pathway.
Osteoporosis is a common disease causing fracture in older populations. Abnormal apoptosis of osteoblasts contributes to the genesis of osteoporosis. Inhibiting apoptosis of osteoblasts provides a promising strategy to prevent osteoporosis. The proliferation of osteoblasts isolated from osteoporotic patients or healthy subjects was determined by MTT assay. Apoptosis was determined by Annexin V/PI assay. Protein expression was measured by western blot. The proliferation of osteoblasts isolated from osteoporotic patients was inhibited and the apoptosis level of these cells was higher than the osteoblasts from healthy subjects. Incubation with psoralen or estradiol significantly enhanced the proliferation and decreased the apoptosis level of osteoporotic osteoblasts. Western blot demonstrated that psoralen or estradiol treatment downregulated the expression of IRE1, p-ASK, p-JNK, and Bax. Meanwhile, expression of Bcl-2 was upregulated. Pretreatment by IRE1 agonist tunicamycin or JNK agonist anisomycin attenuated the effect of psoralen on osteoporotic osteoblasts. Psoralen inhibited apoptosis of osteoporotic osteoblasts by regulating IRE1-ASK1-JNK pathway.


SPRR3, a novel miR-338-3p target, regulates the malignant progression of clear cell renal cell carcinoma in vitro via the PI3K/Akt signaling pathway.
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma and has a poor prognosis. However, its underlying mechanisms remain unclear. The present study aimed to evaluate the role of small proline-rich repeat protein 3 (SPRR3) in the proliferation, migration and invasion of ccRCC cells and to investigate its upstream and downstream regulatory mechanisms. Survival analysis was performed using the UALCAN website based on the The Cancer Genome Atlas database. Normal renal cell line HK-2 and ccRCC cell lines (786-O, CaKi-1 and UMRC-2) were used. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect mRNA and microRNA (miRNA) levels. Western blotting was used to detect protein levels. Cell Counting Kit-8 and colony formation assays, a wound healing assay and a Transwell invasion assay were used to assess the proliferation, migration and invasion of ccRCC cells, respectively. Transfection of overexpression plasmids and small interfering RNAs were used to upregulate and knockdown SPRR3 expression, respectively. Transfection of miRNA-mimics was used to overexpress miR-338-3p. A luciferase reporter gene assay was used to verify the predicted binding relationship between SPRR3 mRNA and miR-338-3p. The results indicated the following: i) SPRR3 was a risk factor for the survival of patients with ccRCC, and was upregulated in ccRCC cell lines; ii) SPRR3 promoted the proliferation, migration and invasion of ccRCC cells; iii) SPRR3 regulated the tumor phenotypes of ccRCC cells via the PI3K/Akt pathway; iv) miR-338-3p directly targeted SPRR3 mRNA and negatively regulated SPRR3 expression; and v) miR-338-3p inhibited the PI3K/Akt pathway and the tumor phenotypes of ccRCC cells by downregulating SPRR3. In conclusion, SPRR3, as a novel target of miR-338-3p, regulated the proliferation, migration and invasion of ccRCC cells via the PI3K/Akt pathway; this finding not only enriches our understanding of the mechanism underlying ccRCC development, but also demonstrates a potential novel therapeutic target for this disease.


Antigen receptors on murine T lymphocytes in contact sensitivity. III. Mechanism of negative feedback regulation by auto-anti-idiotypic antibody.
Contact sensitivity (CS) to 2,4-dinitrofluorobenzene (DNFB) is maximal 6 d after sensitization but declines rapidly. Previous studies have shown that this rapid decline is due to auto-anti-idiotypic (anti-Id) antibodies produced by the host. The present study was done to investigate the mechanism(s) involved in his down-regulation of the effector phase of the CS reaction. Using transfer of CS to mimic the natural effector phase, we found that the inhibition of transfer by treating DNFB-sensitized lymph node (LN) cells with either auto-anti-Id or syngeneic anti-Id serum is complement (C) independent. This inhibition requires Ia+ T cells in the immune population. Depleting immune LN cells of Ia+ T cells rendered them insensitive to inhibition by anti-Id alone, although the same population is inhibited by anti-Id plus C. This cell population is rendered sensitive to inhibited by anti-Id alone by addition of untreated DNFB-sensitized LN cells, but not by addition of normal LN cells. Further studies showed that the suppression of immunity by anti-Id-activated Ia+ T cells is not systemic, but rather occurs locally at the skin test site and is antigen nonspecific. We interpret these data to indicate that the natural regulation of CS to DNFB by auto-anti-Id antibodies is an active process that involves a negative feedback regulatory loop.


Prenatal diagnosis of 17q12 duplication and deletion syndrome in two fetuses with congenital anomalies.
The objective of this study was to characterize the genetic abnormalities in two fetuses with congenital anomalies in prenatal screening. The mother of Fetus 1 was 26 years old and had a second trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound and magnetic resonance imaging (MRI) at 28 weeks of gestation showed mild ventriculomegaly, microcephaly, and agenesis of the corpus callosum. The mother of Fetus 2 was 25 years old and also had a second trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound at 32 weeks of gestation showed the presence of hyperechogenic and enlarged kidneys with multicystic renal dysplasia bilaterally and a persistent left superior vena cava (PLSVC). Both pregnant women underwent cord blood samplings because of the abnormal imaging results. Karyotype analysis revealed normal results in the two fetuses. Chromosome microarray analysis (CMA) was then performed to provide genetic analysis of the cord blood and parental blood samples. Ultimately, the pregnancies were both terminated. CMA detected a 1.56-Mb duplication at 17q12 in Fetus 1 and a 1.93-Mb deletion of 17q12 in Fetus 2. Both the duplicated and deleted regions included the HNF1B and LHX1 genes. Neither the duplication nor deletion was inherited from the parents. This study is the first to report the prenatal diagnosis of a 17q12 duplication syndrome. Our results further confirmed that genes in this region, including HNF1B and LHX1, are essential for normal brain and kidney development, and also indicated some genes that may be associated with the cardiovascular abnormality. Combined with imaging examination, the use of CMA will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.


Two-dimensional small-scale variability of pore water phosphate in freshwater lakes: results from a novel dialysis sampler.
Vertical concentration profiles of soluble reactive phosphorus (SRP) in the upper sedimentary zone of freshwater lakes are an important means for studying internal phosphorus (P) loading and to gain insight into early diagenetic processes. The interpretation of such pore water profiles generally neglects the occurrence of horizontal variability at a specific sampling site. To further examine this variability, we have designed a novel two-dimensional sampler (2D peeper) consisting of 2280 chambers at a spatial resolution of 9 mm providing a sampling area of 43 x 44 cm. This new device was deployed in three eutrophic lakes in north-eastern Germany. The resulting 2D images of the SRP concentrations, diffusive fluxes, and turnover rates revealed systematic vertical and horizontal structures with local niches of increased phosphorus release. Thus, the extrapolation of P flux calculations based on one-dimensional pore water profiles may lead to a considerable error. The observed small-scale horizontal heterogeneity, probably mainly caused by organisms, was larger in the biologically more active Lake Müllrose and Süsser See than in the deeper Arendsee where meio- and macrozoobenthos were missing. In all cases, the variability was highest at the sediment-water interface and diminished with sediment depth.


NF-κB participates in chemokine receptor 7-mediated cell survival in metastatic squamous cell carcinoma of the head and neck.
Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signal pathway to promote the invasion and survival of SCCHN cells. Since nuclear factor-kappa B (NF-κB) is shown to be the downstream signal molecule of PI3K/Akt in many tumors, we investigated whether it also exists in the CCR7 pathway in SCCHN, and the relationship between NF-κB and PI3K/Akt/mTOR, and the role it plays in SCCHN. We assayed the phosphorylation of the inhibitor of NF-κB (IκBα), the NF-κB DNA-binding capacity and location. The results showed that the interaction between CCR7 and the ligand for CCR7, CCL19, induces phosphorylation of IκBα, causes NF-κB to translocate to the nucleus and raises the DNA-binding capacity of NF-κB. The phosphorylation and DNA-binding capacity were abolished by the inhibition of CCR7, PI3K, Akt and mTOR. Further research demonstrated that inhibitors of NF-κB and CCR7-PI3K attenuate the survival of CCR7-mediated cells, causing decreased viability, increased apoptosis and increased cell cycle arrest in SCCHN cells. In clinical samples from 78 patients, immunohistochemical assay also showed that CCR7 and NF-κB are not only highly expressed in SCCHN, but also correlated with each other, and related to lymph node metastasis and clinical stage. Together, our data indicate that NF-κB is activated by CCR7 via PI3K/Akt/mTOR, and this signal pathway plays an important role in regulating the cell survival and prognosis of SCCHN.


Cytoplasmic bar-like structures of alveolar type II cells: an ultrastructural study in freshly isolated cells from rat lungs.
Bar-like structures are tubular cytoplasmic inclusions found in situ in pulmonary epithelial type II cells of several animal species. The physiological significance and mode of formation of these inclusions are not fully established. In this paper, we describe bar-like structures as found in freshly isolated type II cells from rat lungs. Pulmonary cells were dissociated from the tissue with elastase and separated on a discontinuous density gradient of Percoll. The complete isolation procedure yielded 17 X 10(6) type II cells per animal (purity = 80%). Either from the crude cell suspensions or the purified preparations, only a small fraction of the type II cell population harbored the inclusions (less than 5%). It is shown that the bounding membranes of the bar-like structures can derive from the endoplasmic reticulum, the nuclear membrane, or the Golgi apparatus. Occasional connections with lamellar bodies were observed, and different levels of complexity in the bar-like structures were also found. The apparent rigid conformation and the orientation of the bar-like structures were taken as evidence for a role of the cytoskeleton in their formation. Because the inclusions do not appear to be new organelles or cellular structures performing a specific function, we propose that their formation may be a transient and limited cellular event in normal cells. However, the stabilization and the generation of the osmiophilic structures, as well as their overproduction, may reflect alterations of the normal physiology of the type II cells.


The effect of the GABA-agonist, progabide, on benign essential tremor. A controlled clinical trial.
In a double-blind crossover trial of two 2-week treatment periods, to which 18 patients with benign essential tremor were admitted, there was no statistically significant different between progabide 11.4-20.2 mg/kg X day (median 14.2 mg/kg X day) and placebo in tremor score and tremor amplitude. However, there was a definite placebo and period effect with reduction of tremor score and tremor amplitude during the second period of treatment compared to the first period of treatment, regardless of the treatment regime. This was presumably a result of prolonged treatment and habituation to the test situation and not an effect of the active drug. No side-effects were registered and no laboratory abnormalities were seen.


Clinical Utility of Genetic Testing in the Precision Diagnosis and Management of Pediatric Patients with Kidney and Urinary Tract Diseases.
As genetic testing increasingly integrates into the practice of nephrology, our understanding of the basis of many kidney disorders has exponentially increased. Given this, we recently initiated a Renal Genetics Clinic (RGC) at our large, urban children's hospital for patients with kidney disorders. Genetic testing was performed in Clinical Laboratory Improvement Amendments-certified laboratories using single gene testing, multigene panels, chromosomal microarray, or exome sequencing. A total of 192 patients were evaluated in this clinic, with cystic kidney disease (49/192) being the most common reason for referral, followed by congenital anomalies of the kidney and urinary tract (41/192) and hematuria (38/192). Genetic testing was performed for 158 patients, with an overall diagnostic yield of 81 out of 158 (51%). In the 16 out of 81 (20%) of patients who reached a genetic diagnosis, medical or surgical treatment of the patients were affected, and previous clinical diagnoses were changed to more accurate genetic diagnoses in 12 of 81 (15%) patients. Our genetic testing provided an accurate diagnosis for children and, in some cases, led to further diagnoses in seemingly asymptomatic family members and changes to overall medical management. Genetic testing, as facilitated by such a specialized clinical setting, thus appears to have clear utility in the diagnosis and counseling of patients with a wide range of kidney manifestations.


Infrared photodissociation spectroscopy of protonated ammonia cluster ions, NH4+(NH3)n (n=5-8), by using infrared free electron laser.
Infrared photodissociation action spectra of protonated ammonia cluster ions, NH(4) (+)(NH(3))(n) (n=5-8), were measured in the range of 1020-1210 cm(-1) by using a tunable infrared free electron laser. Analyses by the density functional theory (DFT) show that the spectral features observed can be assigned to the nu(2) vibrational mode of the NH(3) molecules in NH(4) (+)(NH(3))(n). Size dependence of the spectra supports structural models obtained by the DFT calculations, in which the NH(4) (+) ion is solvated by the four nearest-neighbor NH(3) molecules. For NH(4) (+)(NH(3))(5), the spectrum between 1000 and 1700 cm(-1) was measured. The nu(4) bands of the NH(3) molecules and the NH(4) (+) ion were found in the range of 1420-1700 cm(-1).


Liver Transplant and Improvements in Cholesterol Biosynthesis Defects: A Case Report of Smith-Lemli-Opitz Syndrome.
Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic disease characterized by mental retardation and multiple congenital anomalies. The main pathology is the lack of the enzyme 3β-hydroxysterol Δ7-reductase, which is the last enzymatic step in cholesterol synthesis, ending with a low cholesterol level. Cholesterol is vitally important in cell membranes and myelination of the nervous system. The cholesterol level affects many systems of the body, especially the nervous system. The cause of liver involvement in Smith-Lemli-Opitz syndrome is unclear, and many hypotheses have been suggested. Here, we present the early results of a patient with Smith-Lemli-Opitz syndrome who underwent living-donor liver transplant due to cirrhosis. As a result of liver transplant, normal cholesterol levels were shown, as well as improvements in the patient's neurodevelopment and behavior. Early liver transplant may be considered for patients with a defect of cholesterol biosynthesis, even in the absence of cirrhosis, and may be a future treatment option to prevent risks of neurologic deterioration.


Transplanted olfactory ensheathing cells reduce retinal degeneration in Royal College of Surgeons rats.
Retinitis pigmentosa (RP) is a group of genetic disorders and a slow loss of vision that is caused by a cascade of retinal degenerative events. We examined whether these retinal degenerative events were reduced after cultured mixtures of adult olfactory ensheathing cells (OECs) and olfactory nerve fibroblasts (ONFs) were transplanted into the subretinal space of 1-month-old RCS rat, a classic model of RP. The changes in retinal photoreceptors and Müller cells of RCS rats after cell transplantation were observed by the expression of recoverin and glial fibrillary acidic protein (GFAP), counting peanut agglutinin (PNA)-positive cone outer segments and calculating the relative apoptotic area. The retinal function was also evaluated by Flash electroretinography (ERG). To further investigate the mechanisms, by which OECs/ONFs play important roles in the transplanted retinas, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) secretion of the cultured cells were analyzed by ELISA. The ability of OECs/ONFs to ingest porcine retinal outer segments and the amount of phagocytosis were compared with retinal pigment epithelium (RPE) cells. Our research showed that the transplantation of OECs/ONFs mixtures restored recoverin expression, protected retinal outer segments, increased PNA-positive cone outer segments, reduced caspase-positive apoptotic figures, downregulated GFAP, and maintained the b-wave of the ERG. Cultured OECs/ONFs expressed and secreted NGF, BDNF, and bFGF which made contributions to assist survival of the photoreceptors. An in vitro phagocytosis assay showed that OECs, but not ONFs, phagocytosed porcine retinal outer segments, and the phagocytic ability of OECs was even superior to that of RPE cells. These findings demonstrate that transplantation of OECs/ONFs cleaned up the accumulated debris in subretinal space, and provided an intrinsic continuous supply of neurotrophic factors. It suggested that transplantation of OECs/ONFs might be a possible future route for protection of the retina and reducing retinal degeneration in RP.