Social and geographical factors affecting access to treatment of colorectal cancer: a cancer registry study.
Cancer outcomes vary between and within countries with patients from deprived backgrounds known to have inferior survival. The authors set out to explore the effect of deprivation in relation to the accessibility of hospitals offering diagnostic and therapeutic services on stage at presentation and receipt of treatment. Analysis of a Cancer Registry Database. Data included stage and treatment details from the first 6 months. The socioeconomic status of the immediate area of residence and the travel time from home to hospital was derived from the postcode. Population-based study of patients resident in a large area in the north of England. 39 619 patients with colorectal cancer diagnosed between 1994 and 2002. Stage of diagnosis and receipt of treatment in relation to deprivation and distance from hospital. Patients in the most deprived quartile were significantly more likely to be diagnosed at stage 4 for rectal cancer (OR 1.516, p<0.05) but less so for colonic cancer. There was a trend for both sites for patients in the most deprived quartile to be less likely to receive chemotherapy for stage 4 disease. Patients with colonic cancer were very significantly less likely to receive any treatment if they came from any but the most affluent area (ORs 0.639, 0.603 and 0.544 in increasingly deprived quartiles), this may have been exacerbated if the hospital was distant from their residence (OR for forth quartile for both travel and deprivation 0.731, not significant). The effect was less for rectal cancer and no effect of distance was seen. Residing in a deprived area is associated with tendencies to higher stage at diagnosis and especially in the case of colonic cancer to reduced receipt of treatment. These observations are consistent with other findings and indicate that access to diagnosis requires further investigation.


Antimicrobial susceptibility and tetracycline resistance determinant genotyping of Gallibacterium anatis.
The present investigation was undertaken to assess the antimicrobial susceptibility of a collection of 58 Gallibacterium isolates. All strains were tested by the broth dilution method using the veterinary fastidious medium. A total of 46 field strains were tested, whereof 23 were clinical isolates from 10 Mexican layer flocks and another 23 isolates originated from 13 clinically healthy poultry flocks in Denmark. In addition, 12 Gallibacterium reference strains that had been isolated some 30-40 years ago were included. The 58 strains were tested against 23 compounds of different classes. Multidrug resistance (resistance towards≥three drugs) was observed for 65% of the field strains and only two strains were susceptible to all compounds. Most prominently, resistance to tetracycline and sulfamethoxazole was observed in 92% and 97% of the field strains, respectively. For comparison these figures were 67% and 42%, respectively, for the reference strains. Genotyping of tetracycline resistance determinants was performed with primers specific for tet(A-E, H, K-M, O). Strains positive for tet(B), tet(H) and tet(L) were identified, however, in 20 out of 49 tetracycline resistant strains no determinant was identified. This is the first study to determine the antimicrobial susceptibility of Gallibacterium anatis by MIC revealing that multidrug resistance is very common among G. anatis field isolates. tet(B) was by far the most common determinant identified but future work should aim at identifying the tetracycline resistance determinants in the remaining 41% of strains where no determinant was assigned.


Mutual antagonism between aryl hydrocarbon receptor and hypoxia-inducible factor-1α (AhR/HIF-1α) signaling: Impact on the aging process.
The ambient oxygen level, many environmental toxins, and the rays of ultraviolet light (UV) provide a significant risk for the maintenance of organismal homeostasis. The aryl hydrocarbon receptors (AhR) represent a complex sensor system not only for environmental toxins and UV radiation but also for many endogenous ligands, e.g., L-tryptophan metabolites. The AhR signaling system is evolutionarily conserved and AhR homologs existed as many as 600 million years ago. The ancient atmosphere demanded the evolution of an oxygen-sensing system, i.e., hypoxia-inducible transcription factors (HIF) and their prolyl hydroxylase regulators (PHD). Given that both signaling systems have important roles in embryogenesis, it seems that they have been involved in the evolution of multicellular organisms. The evolutionary origin of the aging process is unknown although it is most likely associated with the evolution of multicellularity. Intriguingly, there is compelling evidence that while HIF-1α signaling extends the lifespan, that of AhR promotes many age-related degenerative processes, e.g., it increases oxidative stress, inhibits autophagy, promotes cellular senescence, and aggravates extracellular matrix degeneration. In contrast, HIF-1α signaling stimulates autophagy, inhibits cellular senescence, and enhances cell proliferation. Interestingly, there is a clear antagonism between the AhR and HIF-1α signaling pathways. For instance, (i) AhR and HIF-1α factors heterodimerize with the same factor, ARNT/HIF-1β, leading to their competition for DNA-binding, (ii) AhR and HIF-1α signaling exert antagonistic effects on autophagy, and (iii) co-chaperone p23 exhibits specific functions in the signaling of AhR and HIF-1α factors. One might speculate that it is the competition between the AhR and HIF-1α signaling pathways that is a driving force in the aging process.


Cloning and study of adult-tissue-specific expression of Sox9 in Cyprinus carpio.
The Sox9 gene is one of the important transcription factors in the development of many tissues and organs, particularly in sex determination and chondrogenesis. We amplified the genomic DNA of Cyprinus carpio using degenerate primers, and found that there were two versions of Sox9 in this species: Sox9a and Sox9b, that differ in having an intron of different length (704 bp and 616 bp, respectively) in the conserved HMG box region that codes for identical amino acid sequences. We used a two-phase rapid amplification of cDNA ends (RACE) for the isolation of full-length cDNA of Sox9b. Sequence analyses revealed a 2447-bp cDNA containing 233-bp 5' untranslated region, a 927-bp 3' untranslated region, including poly(A), and a 1287 bp open reading frame (ORF) encoding a protein of 428 amino acids. The HMG box of 79 amino acid motif was confirmed from positions 96-174. Sequence alignment showed that the identity of amino acids of Sox9 among ten animal species, including C. carpio, is 75%, indicating that the Sox9 gene is evolutionarily quite conserved. The expression level of Sox9b gene varied among several organs of adult C. carpio, with the level of expression being highest in the brain and testis.


Modulation of hypoxia by magnetic nanoparticle hyperthermia to augment therapeutic index.
A hypoxic microenvironment in solid tumors has been known to cause resistance to standard therapies and to increase the malignant potential of tumors. The utilization of magnetic nanoparticle hyperthermia (mNPH) has shown promise in improving therapeutic outcome by (1) killing of hypoxic tumor cells directly and (2) increasing tumor oxygenation and therefore susceptibility to therapies. In this study, the interaction of a hypoxic microenvironment with mNPH efficacy was investigated in a human breast cancer orthotopic xenograft model. Using electron paramagnetic resonance (EPR) to assess in vivo oxygen concentration in tumors repeatedly and non-invasively, we found that mNPH increased tumor pO₂ from 3.5 to 68.8 mmHg on average for up to 10 days. Tumors treated once with mNPH showed growth delay. On Transmission Electron Microscopy, magnetic nanoparticles (mNPs) were localized intracellularly in multiple vesicles in the cytoplasm of cells within tumors 48 h after incubation of mNP. In conclusion, mNPH increased tumor oxygenation in vivo and resulted in decreased growth of hypoxic tumors. Future studies will establish tumor pO₂-guided multimodal therapies, such as mNPH and radiation, to improve therapeutic efficacy.


The progressive development of depression-like behavior in corticosterone-treated rats is paralleled by slowed granule cell maturation and decreased reelin expression in the adult dentate gyrus.
We have hypothesized that the extracellular matrix protein reelin is involved in the pathogenesis of major depression. This hypothesis is based on previous work in which we showed that repeated exposure to the stress hormone corticosterone, which increases depression-like behavior in rodents, also decreases the number of reelin+ cells in specific regions of the hippocampus and decreases hippocampal neurogenesis. In addition, we have found that heterozygous reeler mice, which express approximately 50% of normal brain levels of reelin, are more susceptible to the depressogenic effects of corticosterone than their wild-type counterparts. To further understand the relationship between corticosterone, reelin, and depression, we assessed whether the effects of corticosterone on hippocampal reelin expression and neurogenesis parallel the progressive development of depression-like behavior over a 21-day period. Rats were subjected to 7, 14 or 21 days of repeated corticosterone injections (40 mg/kg, s.c.) or vehicle injections followed by behavioral testing, immunohistochemistry, and Golgi analyses. We found that corticosterone-treated rats showed gradual increases in depression-like behavior over time, which were accompanied by similarly gradual decreases in reelin expression in the dentate subgranular zone and decreases in the number and dendritic complexity of surviving immature dentate granule cells. Interestingly, corticosterone had no significant effect on dendritic complexity in mature granule cells. These results support our hypothesis that reelin plays a role in the pathogenesis of depression and suggest that reelin could be an important target for the development of novel therapeutics for the treatment of depression.


Unusual thrombotic-like retinopathy (Coats' disease) associated with congenital plasminogen deficiency type I.
A new kindred with heterozygous plasminogen deficiency type I is described. The proband, a 17-year-old male, showed a peculiar thrombotic-like retinal picture compatible with Coats' disease. Extensive coagulation studies revealed decreased levels of both plasminogen activity and antigen to about 50% of normal values. Five out of 13 family members from the paternal side showed the same fibrinolytic defect. In two cases, a history of recurrent phlebites of the lower limbs was present. One unaffected patient also had a superficial phlebites at a young age; her plasminogen levels were shown to be within normal limits, but a long-standing oestroprogestinic intake could have influenced and normalized the results. No other family member showed retinal abnormality. This is the first case of hypoplasminogenaemia associated with Coats' disease. A possible role of the fibrinolytic defect in the pathogenesis of this unusual retinopathy is suggested. Finally, the occurrence of thrombotic manifestations in other affected family members supports the opinion that plasminogen deficiency should be considered as a potential risk factor for thrombosis.


Complete colonic duplication presenting as hip fistula in an adult with pelvic malformation: A case report.
Alimentary tract duplication (ATD) is a rare congenital anomaly. Thus, a case of ATD with a complete colonic duplication isolated in the abdominal cavity with a fistula and multiple malformations is very distinctive. These characteristics show the variability of this disease and explain why it tends to be challenging to diagnose and treat. A 25-year-old woman with a history of a fistula opening in her right hip since birth presented with the irregular discharge of foul fluid from the fistula and intermittent abdominal pain. Contrast-enhanced computed tomography and magnetic resonance imaging findings revealed a duplicated tube isolated in her abdominal pelvic cavity along with a pelvic malformation and double ureter. Right foot radiographic examination showed pes cavus. During surgery, the tube appeared to be an almost complete colonic structure and was verified to be connected to the fistula. All of the involved tissue and fistula were removed, and the defect in the pelvic floor was closed by suturing after surgery. After 8 mo, the postoperative follow-up has been uneventful. ATD may be a differential diagnosis in sinus tract cases. Laparoscopy combined with open surgery is a viable treatment option.


Isolation, Identification and Drug Resistance Rates of Bacteria from Pigs in Zhejiang and Surrounding Areas during 2019-2021.
This study aimed to determine the prevalence of bacterial diseases in pig farms in various regions of Zhejiang Province and surrounding areas. A total of 526 samples were collected from 85 pig farms in Zhejiang Province and surrounding areas. In this study, samples were analyzed using bacterial isolation and purification, Gram staining, PCR amplification, and antimicrobial susceptibility testing. A total of 36 Pasteurella multocida (Pm) isolates were detected, with an isolation rate of 6.84%; 37 Bordetella bronchiseptica (Bb) isolates were detected, with an isolation rate of 7.03%; 60 Glasserella parasuis (G. parasuis) isolates were detected, with an isolation rate of 11.41%; 170 Escherichia coli (E. coli) isolates were detected, with an isolation rate of 32.32%; 67 Streptococcus suis (SS) isolates were detected, with an isolation rate of 12.74%; 44 Actinobacillus pleuropneumoniae (APP) isolates were detected, with an isolation rate of 8.37%; and 7 Salmonella enteritis (SE) isolates were detected, with an isolation rate of 1.33%. Antimicrobial drug susceptibility testing against 21 types of antibiotics was carried out on the isolated strains, and the results showed that 228 strains had varying degrees of resistance to 21 antibiotics, including Pm, Bb, E. coli, and APP, with the highest resistance to lincomycin, at 100%. Pm and APP were the most sensitive to cephalothin, with resistance rates of 0. In terms of strains, Pm had the highest overall sensitivity to 21 antibiotics, and E. coli had the highest resistance. In short, bacterial diseases in Zhejiang and the surrounding areas were harmful, and the drug resistance situation was severe. This study provides scientific guidance for the clinical treatment of bacterial diseases.


Robotic prostatectomy outcomes.
The triad of cancer cure, rapid recovery of complete urinary continence, and preservation of sexual function are desirable in the contemporary surgical treatment of the young potent male with prostate cancer. Robotic prostatectomy is a Food and Drug Administration approved approach to radical prostatectomy, and is performed at our institution and elsewhere. We present a critical assessment of reported outcomes using this minimally invasive technique.


Pregnancy outcomes after laparoscopic sleeve gastrectomy among obese patients.
To analyze pregnancy outcomes after laparoscopic sleeve gastrectomy (LSG) according to body mass index (BMI) at conception and the interval between LSG and pregnancy. In a retrospective study, data were obtained for all women who became pregnant after LSG at a center in France between December 2001 and December 2011. Frequencies of perinatal events according to BMI at conception and the interval between LSG and pregnancy were compared. A total of 63 pregnancies occurring in 54 patients were included, among which 52 (83%) occurred after the first postoperative year and 26 (41%) in women who remained obese. Compared with women who were no longer obese at conception, women who were still obese delivered neonates of significantly lower gestational age at birth (P=0.02) and birth weight (P=0.001). Odds of preterm delivery were also increased (odds ratio 4.37, 95% confidence interval 1.17-16.27; P=0.03). Maternal and neonatal outcomes according to the interval between LSG and pregnancy did not differ significantly. Women who remain obese following LSG are at increased risk of adverse outcomes, including low gestational age at birth, low birth weight, and preterm delivery, and should be regarded as a risk group.


Microcapsules of alginate-chitosan--I. A quantitative study of the interaction between alginate and chitosan.
The binding of chitosan to alginate beads was studied quantitatively by using radioactive labelled fractions of chitosan. The alginate-chitosan capsules were made either by dropping a solution of sodium alginate into a solution containing chitosan or by incubating calcium alginate beads in a solution of chitosan. The first procedure yielded a binding of 0.015 microg chitosan per mm2 of capsule surface, while the latter procedure yielded over 2 microg mm(-2). The maximum obtained weight ratio of chitosan to alginate in a microcapsule after 24 h was 0.40. The binding of chitosan was markedly increased by reducing the number average molecular weight of chitosan below 20000 Da and by increasing the porosity of the alginate gel. The porosity was increased by producing homogeneous gels, and by adding calcium chloride to the chitosan solution during the membrane forming stage. The effect of calcium ions on the porosity of the gel was studied by experiments involving release of blue dextran from calcium alginate beads. The binding of chitosan was also found to increase with decreasing fraction of N-acetylations, FA, on chitosan in the range of FA = 0.3 to FA = 0, and with increasing pH in the range from pH 4 to 6. Capsules with a diameter of 500 microm had a higher weight ratio of chitosan to alginate after 24 h of binding than the capsules with the larger diameter of 1500 microm.


Mixed - Lineage Protein kinases (MLKs) in inflammation, metabolism, and other disease states.
Mixed lineage kinases, or MLKs, are members of the MAP kinase kinase kinase (MAP3K) family, which were originally identified among the activators of the major stress-dependent mitogen activated protein kinases (MAPKs), JNK and p38. During stress, the activation of JNK and p38 kinases targets several essential downstream substrates that react in a specific manner to the unique stressor and thus determine the fate of the cell in response to a particular challenge. Recently, the MLK family was identified as a specific modulator of JNK and p38 signaling in metabolic syndrome. Moreover, the MLK family of kinases appears to be involved in a very wide spectrum of disorders. This review discusses the newly identified functions of MLKs in multiple diseases including metabolic disorders, inflammation, cancer, and neurological diseases.


Very high correlations between fresh weight and lipid-adjusted PCB-153 serum concentrations: irrespective of fasting status, age, body mass index, gender, or exposure distributions.
Persistent organochlorine pollutants (POPs) have in epidemiological studies been associated with health hazards. The exposure window might be crucial and it is, accordingly, important to analyze exposure concentrations in samples collected at the window of interest. This makes the use of stored blood samples extremely interesting. However, small blood volumes from stored samples in biobanks means that the researchers in epidemiological studies most often have to select a limited number of biomarkers representing the POP exposure and abstain from analyses of lipid concentrations. This raises the question of the necessity of lipid adjustment. The aim of the present study was to evaluate the correlation between fresh weight and lipid adjusted concentrations. We included data from studies were we have used the PCB congener 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) as a biomarker for POP exposure and where fresh weight as well as lipid adjusted PCB-153 concentrations are known (n=1628). The variety of the cohort members in the different studies gave us the possibility to better understand how well these measures correlate. When all individuals were included in the analyses a correlation coefficient of 0.95 between fresh weight and lipid adjusted serum concentrations was obtained. Restricting the analyses to specific subgroups (based on gender, fasting status, age and BMI) gave correlation coefficients between 0.85 and 0.97. This study does strongly support the use of samples from biobanks in epidemiological studies for analyzing PCBs, at least regarding PCB-153, even though it is not possible to lipid adjust the results.


Experience, expertise, or specialty? Uses and misuses of a reference.
To analyze systematically the manner in which the results of a published study are presented in subsequent publications that refer to it. We identified a convenience sample of 121 scientific papers that referred to an often-cited 1996 study by Kitahata and colleagues. This study reported that greater primary care physician experience with AIDS was associated with lower mortality among their patients with AIDS. We determined the manner in which the results of the Kitahata and coworkers study were presented, the type of article, and whether its focus was on HIV care. Most of the articles reviewed (78%) appropriately referred to the study as evidence of improved outcomes with increasing provider experience. However, 8% of the articles reviewed referred to the study as evidence of improved outcomes with specialty care and 3% referred to it as evidence of the benefits of expert care. Articles that referred to the study as evidence of improved outcomes with specialty care were more likely to be review articles and articles with a non-HIV focus. This study demonstrates that misrepresentation of the findings of published studies is not uncommon. More needs to be done to ensure the accuracy of references in scientific publications.


Calcium buffering in bursting Helix pacemaker neurons.
Bursting pacemaker neurons of the snail Helix pomatia were voltage-clamped and Ca currents in response to depolarizing steps were recorded. Simultaneously, changes in intracellular Ca concentrations were measured using the fluorescent dye fura-2 and a highly sensitive digital camera. Ca influx through voltage-gated channels induced a spatially non-uniform increase in intracellular Ca. The Ca signals decayed with a time constant of about 5 s. By increasing the concentration of the indicator dye, its Ca-buffering capacity was enhanced and Ca transients in response to depolarization were diminished. Thereby, the endogenous Ca buffer capacity could be determined and was calculated to be about 480 buffered ions for every free Ca ion. The buffer capacity did not vary significantly with the amount of Ca influx within the range tested, suggesting that the buffer is not saturated at Ca concentrations of up to 1 microM.


Abrupt decrease in synaptic inhibition in the postnatal rat olfactory bulb.
Olfactory bulb responses to paired-pulse stimulation of the lateral olfactory tract were examined in urethane-anesthetized rats, aged 5 days to adult. Brief inter-pulse intervals resulted in a depression of test responses at all ages. The magnitude of this depression decreased dramatically between postnatal days 19 and 20 to approach adult levels. Longer inter-pulse intervals resulted in a facilitation of test response amplitude in adult animals. This facilitation was evident at adult levels by postnatal day 10. These results suggest that both inhibitory and facilitatory synaptic mechanisms appear early in the course of rat olfactory bulb development. Furthermore, presumed granule cell-mediated inhibition is present at unusually high levels in the developing bulb, decreasing sharply between days 19 and 20.


Reconstructing migratory network nodes to improve environmental management and conservation decisions: A case study of the common quail Coturnix coturnix as a biosensor.
Public health risks are related to environmental management practices, and are essential to the understanding of ecosystem dynamics. The expansion of urbanized areas affects migratory bird networks and can impact the population sizes of migratory species and, in parallel, increase the risk of diseases carried by migratory species spreading into urban areas. Taking the European population of the common quail as a case study, we reconstructed its migratory network between Europe and the Maghreb using quail recoveries from the Italian Bird Ringing Scheme. We showed that soils at the central European migratory node have been degraded through urbanization and reforestation, decreasing the number of successful migrations over this area. Conceptual models incorporating the One Health approach, natural and social capital, landscape infrastructure, and ecosystem services could explain the relationships between climate warming and extensively developed, intensively developed, and urbanized ecosystems. Failed migratory flights of quail over central Europe highlight not only the problems of infrastructure design and their impact on ecosystems services, but also on One Health parameters. The damage to migratory network nodes presents a global threat to biodiversity and can increase the spread of diseases. To address this challenge we propose: i) improvements in land quality; ii) transboundary migration monitoring programmes; and iii) management plans for migratory birds - the overall aim being to optimize infrastructures to improve the quality of human life. Lessons drawn from a better understanding of the migratory networks of quail in relation to different ecosystems provide useful tools to improve infrastructure management and political decision making processes.


[Unemployment and Health: An overview of current research results and data from the 2010 and 2012 German Health Update].
This study analyzes the association of unemployment and health using national and international research data. It is based on data from the 2010 and 2012 German Health Update (GEDA), conducted by the Robert Koch Institute. For our analysis, participants aged from 18 to 64 years were selected if they gave information on their unemployment experiences within the five years prior to the study (n = 31,955). The results show that the self-rated health of the unemployed in Germany is significantly worse compared to the workforce. Additionally, the unemployed suffer from medically diagnosed depression. The association of unemployment and health is more pronounced in men than in women for all major outcomes. When compared to workers of the same age, the unemployed smoke more frequently and do less sports. Regarding alcohol consumption, no systematic relationship was found. While the use of medical screening measures for the early detection of diseases is lower among the unemployed than among the employed, they visit general practitioners and hospitals more often than their counterparts. Overall, our findings suggest that unemployed people should remain an important target group of preventive measures in Germany and that the corresponding measures should be intensified.


[Comparative psychological studies on disease management and attitude to life in patients with hemophilia with special reference to their motor disabilities].
The motor skills of 39 haemofiliacs are examined under the question to what extent they are permanently disabled and how this disability is subjectively experienced. Besides the question is followed how far the restriction of the motorial functions in relation to other psychological stress within this illness reduces and neurotizises their attitude to life. The results are discussed unter depth-psychological points of view and with regard to the Psychology of Neurosis.


Oral granisetron--simple and effective: a preliminary report. The Granisetron Study Group.
This randomised, double-blind, study was carried out in 930 patients in order to examine the efficacy and safety of oral granisetron in the dose range 0.25, 0.5, 1.0 and 2.0 mg twice daily. Oral granisetron was administered for either 7 or 14 days according to the chemotherapy regimen used. A total of 930 patients were enrolled into this study in order to be able to detect a difference of 15% between groups (80% power). The preliminary results showed that at 7 days efficacy was significantly greater for 1.0 mg b.d. (58.5%) than for 0.25 mg b.d. (43.7%) and indicated that, of the doses examined, the 1.0 mg b.d. dose was optimal in patients receiving moderately emetogenic chemotherapy. In agreement with this there were more withdrawals from the 0.25 and 0.5 mg groups due to lack of efficacy. The adverse events most frequently reported (in greater than 5% of patients) were constipation, headache, abdominal pain, fever, leucopenia and asthenia. The latter three are recognised side effects of the primary disease and of chemotherapy. The incidence of headache was similar to that seen in previous granisetron studies. Abdominal pain may have been related to constipation. The incidence of constipation (25.9%) was higher than that reported in previous granisetron studies but was not dose related. Thus oral granisetron at 1.0 mg twice daily is an effective antiemetic, offering a convenient dosing regimen without significant adverse events.


Raised intracranial pressure and brain edema.
Acutely increased intracranial pressure (ICP) is a life-threatening neurosurgical emergency. Optimal management strategy is selected according to the causative process. Typical causes are intracranial bleeds like traumatic subdural, epidural, or intracerebral hematoma (ICH); spontaneous ICH, intraventricular hemorrhage, subarachnoid hemorrhage, and hydrocephalus. When occurring without significant brain injury and treated effectively before herniation, a full recovery can be expected. In intraparenchymal injuries a full recovery is unlikely since dead cells in the central nervous system leave an "empty hole," to be replaced by cerebrospinal fluid. The clinical recovery is based on the surviving cells that are able to make new synapses. Surgery may decrease ICP by removing significant mass effect. In all conditions, when notable injury of brain parenchyma occurs, brain edema may gradually increase ICP and further worsen the clinical condition. This is seen typically in large brain infarctions when the formation of brain edema may lead to increased ICP for hours and days. Brain edema is traditionally classified as vasogenic or cytotoxic but according to current knowledge is rather a continuum, starting with cytotoxic cell swelling followed by ionic edema and then vasogenic edema. Here we review the causes of increased ICP, including mechanisms of brain edema, with clinical examples.


Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation.
Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCFFbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCFFbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCFFbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCFFbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCFFbxo4-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.


Efficacy of tocilizumab for fulminant multiple sclerosis with a tumefactive cervical lesion: A 12-year-old boy.
Fulminant demyelinating disease including acute disseminating encephalitis, multiple sclerosis (MS) variants, and neuromyelitis optica spectrum disorder (NMOSD) are often managed with similar acute treatment such as intravenous methylprednisolone and plasma exchange. On the other hand, long-term management varies. The choice of the drug is based on several factors including the activity and severity of the disease course. Tocilizumab (TCZ), which is a humanized anti-interleukin-6 receptor antibody, is one of the promising therapies for NMOSD because of decreasing the relapse rates and possibly the neurological disability. However, the efficacy of TCZ for MS with tumefactive lesion is unknown. Here, we describe the clinical course of a 12-year-old Japanese boy who was diagnosed with fulminant MS with a tumefactive cervical lesion. Our case was refractory to aggressive immunosuppressive therapies and developed dependent on an intermediate dose of oral prednisolone (PSL) for relapse prevention. His neurological condition worsened with every attempt of tapering the PSL dose. Thus, we started treatment with tocilizumab, which allowed of tapering of the PSL dose without his symptom exacerbations, and effectively improved his Expanded Disability Status Scale score. Our findings may indicate that TCZ is effective for fulminant MS patients with a tumefactive cervical lesion.


A comparison of the energy and nitrogen metabolism of broilers selected for increased growth rate, food consumption and conversion of food to gain.
Calorimetric measurements were made on 5-week-old male chickens sampled from the third generation of three lines selected for either increased live-weight gain (W), food consumption (F), or food conversion efficiency (E). A control line (C) was also measured. 2. Food intake and food conversion ratio were greater (P less than 0-05) in the F line than in the E anc C lines. 3. Metabolisability of the diet was 0-8% higher in the E line than in the other lines. 4. Metabolisable energy (ME) intake and heat production were greater (P less than 0-05) in the F line than in the E and C lines, and energy balance was greater (P less than 0-05) in the F than in the W and E lines. 5. During starvation, excreta energy and heat production were greater (P less than 0-05) in the F than the other lines. 6. Availability of ME (net energy) was the same (85%) for all lines but calculated daily maintenance energy requirements (kJ ME/kgW) were W, 860; F, 937; E, 796 and C, 810. 7. By 9 weeks the F line contained more fat and less water than lines E and C.


Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness.
Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues.


Left-right pairing at the crest synapses of rat interpeduncular nucleus.
Synaptic terminals of the habenulo-interpeduncular axons in rat interpeduncular nucleus are demonstrated by electron-microscopic autoradiography following [3H]leucine injection into the habenula. The endings are of two types, S and crest synapses. Previous descriptions of the S synapses based on indirect identification were confirmed. The crest synapses in the interpeduncular nucleus consist of two habenular afferents contacting a narrowed dendrite. Injection of both habenulae with radiolabeled amino acid resulted in autoradiographic labeling of both axons at 48% of individual crest synapses, and of one axon at 39%. However, when only one habenula was injected, no more than one axon was labeled at individual crest synapses; this occurred at 59%. Interpretation of unlabeled endings is possible using the "detection rate" of the method (per cent ratio of labeled to total endings). The detection rate, which can be determined for the bilateral injection case, allows recalculation of the raw data for the unilateral injection case. Left-right pairing of habenular afferents actually occurs at approximately 90% of crest synapses. The use of detection rates in this way, additionally exemplified by analysis of an electron-microscopic degeneration study, is also important in many other applications of both of these experimental neuroanatomical methods, especially when comparisons between two sets of data are made. The conclusions of studies which have not taken this problem into account must be interpreted with caution.


Initiation of high frequency multi-drug resistance following kinase targeting by siRNAs.
The sequential use of non cross-resistant cytotoxic agents is the standard of care for advanced solid tumors in order to enhance survival and optimise quality of life. Nevertheless, drug resistance to non cross-resistant agents is commonly witnessed, with clinical response rates to non cross-resistant regimens declining as the disease advances. Expression of ABC transporters is unlikely to fully explain this phenomenon, and a clear molecular explanation for this process remains uncertain. A statistical analysis of a recently published RNA interference screen targeting 779 kinases in three cell lines deriving from different tumor types reveals a significant correlation between resistance to paclitaxel and a non cross-resistant cytotoxic agent. Furthermore, 20% of kinases that promote resistance to paclitaxel when targeted by RNAi also promote resistance to a non cross-resistant agent within that same cell line, consistent with a tissue-type dependence of multi-drug resistance. Conversely, paclitaxel-specific resistance and sensitising kinases occur less frequently than expected. This indicates that several cell line specific kinases may regulate multi-drug resistance and provide a potential explanation for the phenomenon of drug resistance to non cross-resistant agents witnessed in oncology practice. Furthermore, this work supports efforts to identify common pathways of drug response for future drug discovery programmes.


Fabrication and Compressive Properties of Low to Medium Porosity Closed-Cell Porous Aluminum Using PMMA Space Holder Technique.
In recent years, closed-cell porous Aluminum (Al) has drawn increasing attention, particularly in the applications requiring reduced weight and energy absorption capability such as in the automotive and aerospace industries. In the present work, porous Al with closed-cell structure was successfully fabricated by powder metallurgy technique using PMMA as a space holder. The effects of the amount of PMMA powder on the porosity, density, microstructure and compressive behaviors of the porous specimens were systematically evaluated. The results showed that closed-cell porous Al having different porosities (12%-32%) and densities (1.6478 g/cm³, 1.5125 g/cm³ and 1.305 g/cm³) could be produced by varying the amount of PMMA (20-30 wt %). Meanwhile, the compressive behavior results demonstrated that the plateau stress decreased and the energy absorption capacity increased with increasing amount of PMMA. However, the maximum energy absorption capacity was achieved in the closed-cell porous Al with the addition of 25 wt % PMMA. Therefore, fabrication of closed-cell porous Al using 25 wt % PMMA is considered as the optimal condition in the present study since the resultant closed-cell porous Al possessed good combinations of porosity, density and plateau stress, as well as energy absorption capacity.


Issues underlying use of biosensors to measure metal bioavailability.
Heavy metal-mediated toxicity in the environment is dependent on bioavailable metal concentrations both internal and external to microbial cells. Both internal and external metal bioavailability are influenced by multiple factors in the soil environment. External factors include pH, redox potential, ionic strength, organic matter and clay content. The internal bioavailable metal concentration is dependent on both the aforementioned external factors, as well as metal uptake and efflux activities that are specific for each microorganism. The metal-specific biosensors discussed in this article can be used to measure internal metal bioavailability.


MRI evaluation of microvascular obstruction in experimental reperfused acute myocardial infarction using a T1 and T2 preparation pulse sequence.
To investigate a T1 and T2 preparation pulse sequence to evaluate microvascular obstruction (MO) in a porcine model of reperfused acute myocardial infarction (AMI). A total of 14 pigs with reperfused AMI underwent MRI examinations at baseline and three to four hours after reperfusion. MRI scans included a left ventricular functional study, T1 and T2 measurement on a 1.5T MRI system. At reperfusion, first-pass myocardial perfusion (FPMP) images were obtained after bolus injection of gadopentetate dimeglumine followed by an intravenous drip. Delayed contrast-enhanced MRI (DE-MRI) and T1 measurements were performed 30 and 45 minutes, respectively, after the bolus, during a constant infusion of gadopentetate dimeglumine. In 11 pigs MO was hypoenhanced in FPMP and DE-MRI. In later T1 preparation difference images postcontrast, MO was hyperenhanced while delayed hyperenhanced (DHE) regions appeared dark. MO areas on DE-MRI and T1 images were comparable. T1 reduction (%) postcontrast in MO was small compared to measurements from DHE regions (P < 0.0001) and similar to those from control segments (P = 0.66). Precontrast T1 and T2 values at reperfusion from MO and DHE regions were larger than in control regions. Using T1 preparation under a constant gadopentetate dimeglumine (Gd-DTPA) infusion, delayed imaging at 30 to 45 minutes demonstrates MO as a positive contrast with larger T1 values. Elevated T1 and T2 values in MO precontrast may also help to differentiate them from both control and DHE regions.


In-vitro oocyte maturation: some questions concerning the initiation and prevention of this process in humans.
Human oocytes isolated from healthy non-preovulatory antral follicles which had not been stimulated spontaneously resumed meiosis at a low rate (31%) when compared with those from atretic follicles (73%). Human follicular fluid did not inhibit spontaneous maturation of rat oocytes in vitro, regardless of the quality or maturity of the follicle or the treatment of the patient. In the human, oocyte maturation may involve a stimulatory process as well as a removal of inhibition.


Impact of Neoadjuvant Chemoradiation on Short-Term Outcomes for Esophageal Squamous Cell Carcinoma Patients: A Meta-analysis.
Neoadjuvant chemoradiation (NCRT) has emerged as a component of the standard treatment for esophageal squamous cell carcinoma (SCC). The primary benefit of NCRT is an improvement in long-term survival; however, the impact of NCRT on short-term outcomes is unclear. A comprehensive electronic literature search was performed via the MEDLINE (PubMed), Cochrane Library, and Google Scholar databases through November 2015 for the inclusion of randomized controlled trials (RCTs) that evaluated short-term outcomes of patients administered NCRT followed by surgery compared with surgery alone for resectable esophageal SCC. The main outcome measures were postoperative mortality and morbidity. A meta-analysis was performed using random-effects models to calculate odds ratios (ORs) with 95 % confidence intervals (CIs). Eight RCTs were included, for a total of 1058 patients. Meta-analysis of the overall postoperative mortality and cardiopulmonary complication rates showed that there was a significant increase for patients administered NCRT followed by surgery compared with surgery alone (OR 1.87, 95 % CI 1.07-3.28, p = 0.03, number of patients needed to harm = 33.3; and OR 2.12, 95 % CI 1.03-4.35, p = 0.04, respectively). Dropout before surgery was higher for patients in the NCRT followed by surgery group compared with patients in the surgery-alone group. NCRT has no statistically impact on anastomosis and other complications compared with surgery alone. NCRT for esophageal SCC significantly increases postoperative mortality and cardiopulmonary complications.


Simultaneous detection of mitochondrial viscosity and peroxynitrite in livers from subjects with drug-induced fatty liver disease using a novel fluorescent probe.
Drug-induced fatty liver disease (DIFLD) is a basic clinicopathological example of drug-induced liver injury (DILI). Some drugs can inhibit β-oxidation in hepatocyte mitochondria, leading to steatosis in the liver. Additionally, drug-induced inhibition of β-oxidation and the electron transport chain (ETC) can lead to increased production of reactive oxygen species (ROS) such as peroxynitrite (ONOO-). Therefore, it is reasonable to suspect that compared to a healthy liver, viscosity and ONOO- levels are elevated in livers during DIFLD. A novel, smart, dual-response fluorescent probe-Mito-VO-was designed and synthesized for the simultaneous detection of viscosity and ONOO- content. This probe had a large emission shift of 293 nm and was capable of monitoring the viscosity of, and the ONOO- content in, cell and animal models alike, either individually or simultaneously. For the first time, Mito-VO was successfully used to demonstrate the elevated viscosity and the amount of ONOO- in livers from mice with DIFLD.


Amino acid changes in thiamine-deficient encephalopathy: some implications for the pathogenesis of Friedreich's ataxia.
Thiamine-deficient encephalopathy in the rat is characterized by ataxic gait, loss of righting reflex and curvature of the spine. Neurochemical changes include a diminished activity of cerebral pyruvate decarboxylase leading to abnormal pyruvate oxidation. The present study shows that this defective pyruvate oxidation produces a significant depletion of three important amino acid neurotransmitters, namely gamma aminobutyric acid (GABA), glutamic acid, and aspartic acid. Such changes could lead to severe neuronal dysfunction and the observed neurological symptoms of thiamine deficiency. Some implications for the pathogenesis of Friedreich's ataxia are discussed.


Systemic anti-inflammatory effect induced by antidromic stimulation of the dorsal roots in the rat.
Neurogenic inflammation and other local efferent functions of the capsaicin-sensitive nerve endings is well established. Here, we describe evidence for a systemic neurogenic anti-inflammatory effect initiated in the rat by this local response. A preceding local neurogenic inflammation induced by antidromic stimulation of lumbar dorsal roots inhibited a subsequent inflammatory response due to antidromic stimulation of the contralateral dorsal roots or evoked by subplantar carrageenin injection or instillation of capsaicin solution into the eye. Initiation of these anti-inflammatory responses were prevented by degeneration of the capsaicin-sensitive afferents after perineural capsaicin pre-treatment, but not by bilateral adrenalectomy. These results demonstrate an unorthodox new type of neurohumoral regulatory mechanism of sensory fibres and provide a possible mode of action for the anti-inflammatory effect of counter-irritation and acupuncture.


Radiation oncology as part of medical education-current status and possible digital future prospects.
Education as part of medical education is currently changing rapidly. Not least because of the corona crisis, more and more digital teaching formats and innovative teaching concepts such as the flipped classroom model are finding their way into teaching. We analyzed the acceptance and effectiveness of traditional teaching methods as well as the interest in innovative e‑learning methods among medical students in the field of radiation oncology at the medical school of the Technical University of Munich. We carried out an online-based survey as well as a knowledge test on all students from two terms who had completed the seminar series of radiation oncology. The survey comprised seven questions on the frequency of participation, acceptance, and judgment of the effectiveness in terms of learning and on a potential use of e‑learning methods using a six-point Likert scale. The test consisted of 10 multiple-choice questions. Traditional teaching methods are largely accepted by students and most students consider the current learning format to be effective in terms of the teaching effect in the field of radiation oncology. However, only about 50% of all knowledge questions were answered correctly. The possible use of e‑learning methods was judged critically or desired in roughly equal parts among the students. Traditional seminars enjoy a high level of acceptance among students. Effectiveness with regard to the internalization of content taught, however, should be increased. After all, the future seems to lie in the integration of e‑learning in the form of educational videos and practical seminars.


Variation of Diagnostic Approaches and Treatment Practices for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Among Pediatric Subspecialists.
To assess the diagnostic and treatment practices among a variety of subspecialists at pediatric institutions in the US. Using a web-based survey, we assessed the consultation, diagnostic, and treatment preferences of providers from the different pediatric subspecialties who care for pediatric patients with hemophagocytic lymphohistiocytosis (HLH)/macrophage activating syndrome (MAS). Domains included demographics, provider training level and specialty, experience and comfort level with the diagnosis and treatment of HLH/MAS, and institutional approaches toward the diagnosis and management of HLH/MAS. Participants also were given 2 case scenarios: one describing Epstein-Barr virus-associated HLH and another describing an underlying rheumatologic condition with MAS. Of 263 respondents, 23%, 29%, 39%, and 7% identified as hematology/oncology, rheumatology, general pediatrics/critical care/hospitalist, and allergy/immunology, respectively. For Epstein-Barr virus/HLH, hematology/oncology was the preferred first consultant by most respondents other than rheumatologists, of whom only 47% agreed. For MAS, 92% of respondents from all specialties favored a rheumatology consultation. Preferred diagnostic tests varied by subspecialty, with hematology/oncology more likely than rheumatology to order an infectious workup, natural killer cell function, soluble interleukin-2 receptor, bone marrow biopsy, and genetic testing. First-line therapy also varied, with hematology/oncology preferring dexamethasone and etoposide and rheumatology more often preferring methylprednisolone and anakinra. One-half of respondents were unaware of institutional algorithms for diagnosis and treatment of HLH/MAS. Most (85.6%) favored the development of treatment algorithms for HLH/MAS, and 90% supported a multidisciplinary approach. Current consulting patterns, diagnostic workup, and treatment approaches of HLH/MAS vary by specialty, highlighting the need for standardized management algorithms and institutional multidisciplinary HLH/MAS teams.


The Ovs surface defecting of an S-scheme g-C3N4/H2Ti3O7 nanoheterostructures with accelerated spatial charge transfer.
Semiconductor photocatalysis was a rising star in the sustainable transformation of solar energy for environmental problems governance. Herein, an S-scheme g-C3N4/H2Ti3O7 heterostructure was constructed and applied to tetracycline hydrochloride (TCH) destruction. The g-C3N4/H2Ti3O7 composite has a superior photocatalytic property to degrade TCH in contrast with bare g-C3N4 and H2Ti3O7. The 20% g-C3N4/H2Ti3O7 (CNHTO20) composite exhibited the optimum photocatalytic performance, and the degradation efficiency of 20 mg/L TCH reached 87.37% within 3 h (K = 0.572 min-1). The affluent active sites of the g-C3N4 nanosheet and effective interfacial charge separation of the S-scheme pathway facilitated the excellent performance. Moreover, the ample oxygen vacancies (Ovs) act as the electron mediator, not only reducing the band gap energy by producing the formation of defect levels, but also broadening the photo response range and promoting the interfacial charge transfer. The coordination complexes formed between TCH molecules and Ti (IV) ions in CNHTO20 composites induce strong visible light absorption through ligand-metal charge transfer (LMCT). The Ti4+/Ti3+ metal cycle in CNHTO20 was conducive to the separation of the photogenerated electron-hole pairs on the heterojunction interface as well. The ESR characterization and trapping experiments certified that the dominant substances were OH, O2- and h+. The AQY calculated by the COD removal rate was 0.16%. Conclusively, the S-scheme heterojunction between H2Ti3O7 and g-C3N4 enabled the CNHTO photocatalyst with high redox ability and boosted photocatalytic performance accordingly. This study may shed some enlightenment on the construction of heterojunctions and the realistic treatment of wastewater.


Mutation analysis of the gene encoding the PALB2-binding protein MRG15 in BRCA1/2-negative breast cancer families.
MRG15 is a recently identified member of the BRCA multiprotein complex, essential for the maintenance of the genome integrity and DNA repair. The functional relationship between PALB2 and MRG15 makes MRG15 a strong candidate breast cancer susceptibility gene. We screened affected probands from 232 BRCA1/2-negative breast cancer families for mutations in MRG15. We identified seven previously unreported variants but in silico analyses revealed that none of these variants appears to modify the function of MRG15. Thus, it seems unlikely that any constitutional changes in MRG15 confer an increased risk for breast cancer.


Paediatric minor oral surgical procedures under inhalation sedation and general anaesthetic: a comparison of variety and duration of treatment.
To develop baseline data in relation to paediatric minor oral surgical procedures undertaken with both general anaesthesia and nitrous oxide inhalation sedation within a Hospital Dental Service. Data were collected prospectively over a three-year period from May 2003 to June 2006 for patients attending the Departments of Paediatric Dentistry, Dundee Dental Hospital and Ninewells Hospital, NHS Tayside, Great Britain, for all surgical procedures undertaken with either inhalation sedation or general anaesthetic. Both operator status and the procedure being undertaken were noted. In addition, the operating time was recorded. Data for 166 patients (F: 102; M: 64) with a median age of 12.50 (inter-quartile range 10.00, 14.20) years showed that 195 surgical procedures were undertaken. Of these 160 and 35 were with general anaesthetic and sedation respectively. The surgical removal of impacted, carious and supernumerary unit(s) accounted for 53.8% of all procedures, whilst the exposure of impacted teeth and soft tissue surgery represented 34.9% and 11.3% of procedures respectively. The median surgical time for techniques undertaken with sedation was 30.00 (inter-quartile range 25.00, 43.50) minutes whilst that for general anaesthetic was similar at 30.00 (inter-quartile range 15.25, 40.00) minutes (not statistically significant, (Mann Whitney U, W = 3081.5, P = 0.331). The majority of paediatric minor oral surgical procedures entail surgical exposure or removal of impacted teeth. The median treatment time for most procedures undertaken with either general anaesthetic or nitrous oxide sedation was 30 minutes.


Angiogenesis inhibitor attenuates parathyroid hormone-induced anabolic effect.
In vivo osteogenic responses to anabolic stimuli are expected to be accompanied by angiogenesis as well as in the process of remodeling of bone. Consequently, angiogenesis might play an important role in mediating bone forming stimulating effect of parathyroid hormone (PTH). To investigate this relationship, we used actively growing young Sprague-Dawley rats and CKD-732, one of the angiogenesis inhibitor (AI) to reveal the relationship of angiogenesis in the effect of PTH. The groups were divided as (1) vehicle [VEH group], (2) PTH(1-84) [PTH group], (3) AI alone [AI group], (4) PTH(1-84)+AI concomitance [PTH-AI group] and were treated for 6 weeks. The bone mineral density (BMD) of PTH group was higher than VEH group and the gain of bone mass was attenuated in PTH-AI group. The maximal failure load in PTH group was higher than VEH group, but it was definitely attenuated by concurrent use of AI. Moreover, the toughness showed similar significant deterioration in PTH-AI group. General bone turnover was also significantly decreased in PTH-AI group as shown by the absence of increase in osteocalcin and beta-crosslaps and by decrease in metaphyseal length. The BMD or the biomechanic data of AI only group were similar to the VEH group, suggesting the minimal effect of AI itself on the normal modeling phase of the growing rats. In conclusion, the angiogenesis seemed to contribute to completing the anabolic effect of PTH especially for bone strength.


Generation of embryonic stem cells: limitations of and alternatives to inner cell mass harvest.
Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of the early mammalian embryo. Because of their plasticity and potentially unlimited capacity for self-renewal, ES cells have generated tremendous interest both as models for developmental biology and as possible tools for regenerative medicine. This excitement has been attenuated, however, by scientific, political, and ethical considerations. In this article the authors describe somatic cell nuclear transfer and transcription-induced pluripotency, 2 techniques that have been used in attempts to circumvent the need to derive ES cells by the harvest of embryonic tissue.


Comparative efficacy of omega-3 polyunsaturated fatty acids on major cardiovascular events: A network meta-analysis of randomized controlled trials.
The role of omega-3 polyunsaturated fatty acids (PUFAs) in primary and secondary prevention on major cardiovascular events (MCE) is inconclusive due to the potential heterogeneity in study designs of formulas, dosages, and ratios of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the findings of previous randomized controlled trials (RCTs). Here we conducted a comprehensive narrative review of pre-clinical studies and updated a network meta-analysis (NMA) to determine the comparative efficacy against MCE with different EPA/DHA dosages and formulas. We found that pure EPA was ranked the best option in the secondary prevention (hazard ratio: 0.72, 95% confidence interval: 0.65 to 0.81) from the NMA of 39 RCTs with 88,359 participants. There was no evidence of omega-3 PUFAs' efficacy in primary prevention. The mechanisms of omega-3 PUFAs' cardiovascular protection might link to the effects of anti-inflammation and stabilization of endothelial function from PUFA's derivatives including eicosanoids and the special pre-resolving mediators (SPMs).


Population genomics implies potential public health risk of two non-toxigenic Vibrio cholerae lineages.
Diarrheal cases caused by non-toxigenic Vibrio cholerae have been reported globally. Lineages L3b and L9, characterized as ctxAB-negative and tcpA-positive (CNTP), pose the highest risk and have caused long-term epidemics in different regions worldwide. From 2001 to 2018, two waves (2001-2012 and 2013-2018) of epidemic caused by non-toxigenic V. cholerae occurred in the developed city of Hangzhou, China. In this study, through the integrated analysis of 207 genomes of Hangzhou isolates from these two waves (119 and 88) and 1573 publicly available genomes, we showed that L3b and L9 lineages together caused the second wave as had happened in the first wave, but the dominant lineage shifted from L3b (first wave: 69%) to L9 (second wave: 50%). We further found that the genotype of a key virulence gene, tcpF, in the L9 lineage during the second wave shifted to type I, which may have enhanced bacterial colonization in humans and potentially promoted the pathogenic lineage shift. Moreover, we found that 21% of L3b and L9 isolates had changed to predicted cholera toxin producers, providing evidence that gain of complete CTXφ-carrying ctxAB genes, rather than ctxAB gain in pre-CTXφ-carrying isolates, led to the transition. Taken together, our findings highlight the possible public health risk associated with L3b and L9 lineages due to their potential to cause long-term epidemics and turn into high-virulent cholera toxin producers, which necessitates a more comprehensive and unbiased sampling in further disease control efforts.


Comparison of Opioid Prescription Patterns and Consumption Following Otologic Surgery.
To examine opioid prescribing patterns and consumption among patients undergoing common otologic surgeries. Retrospective cohort study with chart review and telephone survey. Tertiary academic medical center. Retrospective chart review and telephone survey of those undergoing tympanoplasty, tympanomastoidectomy, stapedectomy, and cochlear implantation in 2018. The survey consisted of questions regarding the details of the number of pills taken, duration of opioid use, subjective pain control, the use of over-the-counter pain medications, opioid disposal, and their history of substance abuse. Sixty-one patients were able to be contacted and agreed to participate in the study. Fifty-nine (96.7%) stated that their pain was controlled, and 10 (16.4%) did not take any opioids postoperatively despite their prescription. The mean morphine milligram equivalent (MME) prescribed was 99.9 (44.3) and MME taken was 45.2 (SD 46.3) (p < 0.001). Similarly, the mean number of pills prescribed was 17.8 (SD 8.6) and mean taken was 7.9 (SD 8.3) (p < 0.001). Comparison between males and females regarding MME and pills prescribed and taken were not statistically significantly different (p > 0.05). Analysis of the MME and pills prescribed and taken among the different surgeries (tympanoplasty, stapes surgery, tympanomastoidectomy, and cochlear implantation) revealed no statistically significant interactions (p > 0.05). Pain control was achieved for 50% of patients with 5 pills (MME = 25 mg), for 75% with 12 pills (MME = 60 mg), and for 90% with 24 pills (MME = 135 mg). The opioid epidemic continues to be an ongoing issue in the United States, and prescription opioid abuse is a large contributor. There is increasing literature to suggest a practice of overprescribing in multiple surgical specialties. This same finding appears to be present in common otologic surgeries, where on average patients took less than half of the prescribed MME/pills, and 75% of patients had their pain controlled with 12 pills or fewer. Otolaryngologists performing otologic surgery should strongly consider adjusting their postoperative regimens to reflect these findings. 2b.


Platinum(II)-oxalato complexes of seliciclib (CYC202) derivatives show different cellular effects and lesser adverse effects in mouse lymphoma model than cisplatin.
This work presents a deeper pharmacological evaluation of two formerly prepared and characterized, and highly in vitro cytotoxic platinum(II) oxalato complexes [Pt(ox)(L1)2] (1) and [Pt(ox)(L2)2] (2), containing the derivatives of cyclin-dependent kinase inhibitor (CDKi) seliciclib ((R)-roscovitine, CYC202) coordinating as N-donor carrier ligands, i.e., 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (L1) and 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine (L2). The positive results of in vitro cytotoxicity screening on human cancer cell lines (HeLa, HOS, A2780, A2780R, G361 and MCF7 with IC50 at low micromolar levels) published previously, motivated us to perform extended preclinical in vitro experiments to reveal the mechanisms associated with the induction of cancer cell death. In addition, the in vivo antitumor activity was evaluated using the mouse lymphocytic leukaemia L1210 model. The obtained results revealed that complex 1 exceeds the antitumor effect of cisplatin (as for the extension of life-span of mice) and shows far less adverse effects as compared to reference drug cisplatin. The in vitro and ex vivo studies of cellular effects and molecular mechanisms of cell death induction showed that the mechanism of action of complex 1 is essentially different from that of cisplatin. The obtained results showed a possible way how to obtain antitumor active platinum(II) oxalato complexes with better therapeutic profile than contemporary used platinum-based therapeutics.


SYSTEMIC RISK FACTORS IN BILATERAL PROLIFERATIVE DIABETIC RETINOPATHY REQUIRING VITRECTOMY.
The visual outcome after vitrectomy for proliferative diabetic retinopathy (PDR) is often poor. Bilateral vitrectomy has been especially associated with a poor visual prognosis in patients with PDR. The authors investigated the systemic risk factors for PDR requiring bilateral vitrectomy compared with unilateral vitrectomy. The authors retrospectively reviewed 86 consecutive patients with Type 2 diabetes mellitus with PDR who underwent vitrectomy. These patients were divided into 2 groups: bilateral vitrectomy within 1 year (n = 25) and unilateral vitrectomy (n = 61). The authors compared the systemic risk factors: age, sex, duration of diabetes, hemoglobin A1c, body mass index, estimated glomerular filtration rate, uric albumin, hypertension, dyslipidemia, history of ischemic heart disease, arteriosclerosis obliterans, and smoking. There were significantly more cases with severe renal dysfunction in the bilateral vitrectomy group compared with the unilateral one (estimated glomerular filtration rate <30 mL/minute/1.73 m; bilateral cases = 5/25; unilateral cases = 2/61; P = 0.02). The authors found that severe renal dysfunction may be a risk factor in PDR requiring bilateral vitrectomy, indicating that careful attention needs to be paid to prevent the progression of diabetic retinopathy to severe PDR in the other eye if patients have severe unilateral PDR and severe renal dysfunction.


Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition.
Emerging translational evidence suggests that epigenetic alterations (DNA methylation, miRNA expression, and histone modifications) occur after external stimuli and may contribute to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. This review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. Additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction, n-3 PUFA, Mediterranean diet, vitamin D, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed. Original and review articles encompassing epigenetics and inflammation were screened from major databases (including PubMed, Medline, Science Direct, Scopus, etc.) and analyzed for the writing of the review paper. Although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.


Angiographic study of the tibioperoneal trunks in patients with aorto-iliac occlusive disease.
Knowledge of the normal anatomic characterization of the popliteal artery and its branches is essential as a guide in vascular surgery below the knee. Using radiologic, digital and statistical methods tibioperoneal trunks were studied on 76 preoperative arteriograms, visualizing bilateral configurations of the popliteal artery division, from 46 men and 30 women, with aorto-iliac occlusive disease. The aim of this study has been to evaluate tibioperoneal trunks as to typological (types, frequency of existence, gender and syntopic dimorphisms) and angiometric (length, internal diameter and capacity) aspects. The statistical analysis of tibioperoneal trunks (types, angiometric parameters) did not reveal any gender or syntopic dimorphisms (p > or = 0.05). In both the posterior tibioperoneal trunk (89.47%) or the anterior tibioperoneal trunk (7.89%) short and long ones were found. High correlation coefficients of the symmetry of the left and right vascular patterns were observed (r = 0.80-0.83). In 2.64% of cases tibioperoneal trunks were absent. Two types of posterior tibioperoneal trunk were longer (p < or = 0.01) but they were thinner (p < or = 0.05) than similarly named types of anterior tibioperoneaL trunk. In anterior and posterior tibioperoneal trunks of the short type the diameter of the vessel was statistically larger (p < or = 0.05) than in its long type. The largest capacity was found in the long type and the smallest in the short type of anterior tibioperoneal trunk (p < or = 0.01). These findings have implications in vascular grafting below the knee.


Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products.
It is known that at least some fluorophores can act as 'surrogate' substrates for solute carriers (SLCs) involved in pharmaceutical drug uptake, and this promiscuity is taken to reflect at least a certain structural similarity. As part of a comprehensive study seeking the 'natural' substrates of 'orphan' transporters that also serve to take up pharmaceutical drugs into cells, we have noted that many drugs bear structural similarities to natural products. A cursory inspection of common fluorophores indicates that they too are surprisingly 'drug-like', and they also enter at least some cells. Some are also known to be substrates of efflux transporters. Consequently, we sought to assess the structural similarity of common fluorophores to marketed drugs, endogenous mammalian metabolites, and natural products. We used a set of some 150 fluorophores along with standard fingerprinting methods and the Tanimoto similarity metric. Results: The great majority of fluorophores tested exhibited significant similarity (Tanimoto similarity > 0.75) to at least one drug, as judged via descriptor properties (especially their aromaticity, for identifiable reasons that we explain), by molecular fingerprints, by visual inspection, and via the "quantitative estimate of drug likeness" technique. It is concluded that this set of fluorophores does overlap with a significant part of both the drug space and natural products space. Consequently, fluorophores do indeed offer a much wider opportunity than had possibly been realised to be used as surrogate uptake molecules in the competitive or trans-stimulation assay of membrane transporter activities.


Influence of triethyl phosphate on phosphatase activity in shooting range soil: Isolation of a zinc-resistant bacterium with an acid phosphatase.
Phosphatase-mediated hydrolysis of organic phosphate may be a viable means of stabilizing heavy metals via precipitation as a metal phosphate in bioremediation applications. We investigated the effect of triethyl phosphate (TEP) on soil microbial-phosphatase activity in a heavy-metal contaminated soil. Gaseous TEP has been used at subsurface sites for bioremediation of organic contaminants but not applied in heavy-metal contaminated areas. Little is known about how TEP affects microbial activity in soils and it is postulated that TEP can serve as a phosphate source in nutrient-poor groundwater and soil/sediments. Over a 3-week period, TEP amendment to microcosms containing heavy-metal contaminated soil resulted in increased activity of soil acid-phosphatase and repression of alkaline phosphatase, indicating a stimulatory effect on the microbial population. A soil-free enrichment of microorganisms adapted to heavy-metal and acidic conditions was derived from the TEP-amended soil microcosms using TEP as the sole phosphate source and the selected microbial consortium maintained a high acid-phosphatase activity with repression of alkaline phosphatase. Addition of 5mM zinc to soil-free microcosms had little effect on acid phosphatase but inhibited alkaline phosphatase. One bacterial member from the consortium, identified as Burkholderia cepacia sp., expressed an acid-phosphatase activity uninhibited by high concentrations of zinc and produced a soluble, indigo pigment under phosphate limitation. The pigment was produced in a phosphate-free medium and was not produced in the presence of TEP or phosphate ion, indicative of purple acid-phosphatase types that are pressed by bioavailable phosphate. These results demonstrate that TEP amendment was bioavailable and increased overall phosphatase activity in both soil and soil-free microcosms supporting the possibility of positive outcomes in bioremediation applications.


Rapeseed calcineurin B-like protein CBL4, interacting with CBL-interacting protein kinase CIPK24, modulates salt tolerance in plants.
Calcium is a ubiquitous intracellular secondary messenger in eukaryotes. Upon stress challenge, cytosolic Ca(2+) fluctuation could be sensed and bound by calcineurin B-like proteins (CBLs), which further regulate a group of Ser/Thr protein kinases called CBL-interacting protein kinases (CIPKs) to relay the signal and induce cellular responses. Although the CBL-CIPK network has been demonstrated to play crucial roles in plant development and responses to various environmental stresses in Arabidopsis, little is known about their function in rapeseed. In the present study, we characterized CBL4 gene from rapeseed. We found that CBL4 is localized at the plasma membrane and it interacted with CIPK24 in both yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays. Unlike the orthologs in Arabidopsis, rapeseed CIPK24 did not interact with CBL10. Furthermore, expression of rapeseed CBL4 rescued the salt-sensitive phenotype of sos3-1 mutant and overexpression of rapeseed CBL4 in Arabidopsis showed enhanced tolerance of salt stress than wild-type. Overall, the results clarified the function of CBL4 in rapeseed.


Extracellular matrix metalloproteinase inducer: a novel poor prognostic marker for human seminomas.
Extracellular matrix metalloproteinase inducer (EMMPRIN) is a glycosylated member of the immunoglobulin superfamily whose function in human seminomas is unknown. We have recently determined that EMMPRIN possesses the ability to stimulate fibroblast and endothelial cell matrix metalloproteinase production, and that its expression was frequently up-regulated in several tumours of the urinary system. Thus, EMMPRIN expression might be associated with the progression of human seminomas. The aim of this study was to investigate whether the presence of EMMPRIN in seminoma tissues might help to predict the patients' prognosis. Paraffin-embedded tissues from 65 patients with seminomas and 20 normal testes were processed for immunohistochemical staining using a mouse monoclonal antibody generated against human EMMPRIN, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. In addition, the correlation of EMMPRIN expression with clinicopathologic characteristics and patients' prognosis was also analysed. EMMPRIN was detected in cancerous tissues of 53 patients with seminoma, but not normal testes. Thirty- five patients showed weakly to moderately positive and 18 patients intensely positive expression. Moreover, positive EMMPRIN staining correlated significantly with various clinicopathological factors (increased TNM stage and higher histological differentiation type) as well as decreased tumour-specific survival (log-rank, p=0.02). In particular, EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (p<0.001). EMMPRIN expression in a primary tumour predicts an unfavourable prognosis in human seminoma, suggesting its crucial role in the progression of this tumour.


Pseudomonas tumuqii sp. nov., isolated from greenhouse soil.
A Gram-stain-negative, aerobic, rod-shaped and motile bacterium, named LAMW06T, was isolated from greenhouse soil in Beijing, China. In the 16S rRNA gene sequence comparison, strain LAMW06T had the highest similarity with Pseudomonas cuatrocienegasensis 1NT. Phylogenetic analysis based on the 16S rRNA and three housekeeping gene sequences (gyrB, rpoB and rpoD) indicated that strain represented a member of the genus Pseudomonas. The genome sequence size of the isolate was 5.5 Mb, with a DNA G + C content of 63.5 mol%. The average nucleotide identity and DNA-DNA hybridization values between strain LAMW06T and closely related members of Pseudomonas borbori R-20821T, Pseudomonas taeanensis MS-3T and P. cuatrocienegasensis 1NT were 90.9%, 82.4%, 81.5% and 43.0%, 25.9%, 24.6% respectively. The major fatty acids contained summed feature 3 (C16:1 ω6c and/or C16:1 ω7c), C18:1 ω7c and C16:0. The primary respiratory quinone was ubiquinone-9. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, six aminophospholipids, six phospholipids, one aminolipid and one glycolipid. According to the genotypic, phylogenetic and chemotaxonomic data, strain LAMW06T represents a novel species within the genus Pseudomonas, for which the name Pseudomonas tumuqii sp. nov. is proposed. The type strain is LAMW06T (= GDMCC 1.2003T = KCTC 72829T).


Phenylethylamine and monoamine metabolites in CSF of schizophrenics: effects of neuroleptic treatment.
Phenylethylamine (PEA) and the monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the cerebrospinal fluid (CSF) of nine paranoid schizophrenics before and after three weeks of neuroleptic treatment. Patients were classified according to the Research Diagnostic Criteria and rated by means of the Brief Psychiatric Rating Scale. A significant increase was seen in HVA CSF concentrations during neuroleptic treatment (p less than 0.01). No influence was found on levels of PEA, 5-HIAA, and MHPG. Concentrations of both MHPG and 5-HIAA correlated positively with those of HVA. These results in combination with previous findings do not support the contention that PEA and NA metabolisms are grossly disturbed in paranoid schizophrenics whereas involvement of other neurotransmitters i.e. dopamine, seems more probable.


Lignin-modified metal-organic framework as an effective adsorbent for the removal of methyl orange.
Herein, lignin-modified metal-organic frameworks (NH2-UIO@L) are prepared using a one-step synthesis as sorbents for the removal of organic dyes from water. The introduction of lignin improved the adsorption sites. NH2-UIO@L2 adsorption of MO conforms to Langmuir model, and the adsorption capacity of NH2-UIO@L2 on MO was 214.13 mg·L-1 with an adsorption efficiency up to 99.28 %, which was significantly higher than values for other adsorbents. Due to hydrogen bonds, π-π interactions and electrostatic interactions, MO was effectively removed by NH2-UIO@L2 and its adsorption efficiency is maintained at 90.55 % after six cycles. The adsorption kinetics showed that the NH2-UIO@L2 adsorption of MO was chemical adsorption and controlled by intraparticle diffusion and external mass transfer. Further, the adsorption performance of NH2-UIO@L2 on MO and MB in mixed MO/MB solution was investigated. The adsorption capacity of NH2-UIO@L2 in mixed MO/MB solution was 207.04 mg·L-1 for MO and 243.31 mg·L-1 for MB; the adsorption of NH2-UIO@L2 on MO followed the Dubinin-Radushkevich and pseudo-second-order models, and the adsorption on MB followed the Temkin and pseudo-second-order models. Hydrogen bonds, π-π interactions, and pore filling are all implicated in the removal of MO and MB. In particular, the electrostatic attraction between MB and MO improves the adsorption efficiency of NH2-UIO@L2 on MB. NH2-UIO@L2 has good reusability, maintaining an adsorption efficiency of 97.66 % for MO and up to 99.15 % for MB after six cycles. Its simple preparation and superior adsorption suggest that NH2-UIO@L2 has considerable potential to remove organic dyes from wastewater.


Effects of dry, vacuum, and special bag aging; USDA quality grade; and end-point temperature on yields and eating quality of beef Longissimus lumborum steaks.
This study evaluated the effects of three aging methods: (dry (D), wet (W), and special bag (SB)); two quality grades [USDA Choice((≥Small(50) marbling) and Select); and two cooked end-point temperatures (62.8 °C and 71.1 °C) on physico-chemical traits of instrumental tenderness, color, and sensory properties of Longissimus lumborum beef muscle. Dry-aged loins had higher (P<0.0001) weight loss than W or SB aged loins. However, D and SB aged loins had similar (P>0.05) combined losses. W aged loins had higher (P<0.01) L* values than D or SB aged loins. Warner-Bratzler shear force of steaks was not affected (P>0.05) by aging method or quality grade but increased (P<0.0001) as end-point temperature increased. Sensory panel evaluation also showed no effect (P>0.05) of aging method or quality grade on myofibrillar tenderness, juiciness, connective tissue amount, overall tenderness or off flavor intensity. Steaks cooked to 62.8 °C were juicier (P<0.05) than those cooked to 71.1 °C. Neither D nor SB aging had advantages over W aging.


Conformational dynamics in the disordered region of human CPEB3 linked to memory consolidation.
Current understanding of the molecular basis of memory consolidation points to an important function of amyloid formation by neuronal-specific isoforms of the cytoplasmic polyadenylation element binding (CPEB) protein family. In particular, CPEB is thought to promote memory persistence through formation of self-sustaining prion-like amyloid assemblies at synapses, mediated by its intrinsically disordered region (IDR) and leading to permanent physical alterations at the basis of memory persistence. Although the molecular mechanisms by which amyloid formation takes place in CPEB have been described in invertebrates, the way amyloid formation occurs in the human homolog CPEB3 (hCPEB3) remains unclear. Here, we characterize by NMR spectroscopy the atomic level conformation and ps-ms dynamics of the 426-residue IDR of hCPEB3, which has been associated with episodic memory in humans. We show that the 426-residue N-terminal region of hCPEB3 is a dynamic, intrinsically disordered region (IDR) which lacks stable folded structures. The first 29 residues, M1QDDLLMDKSKTQPQPQQQQRQQQQPQP29, adopt a helical + disordered motif, and residues 86-93: P83QQPPPP93, and 166-175: P166PPPAPAPQP175 form polyproline II (PPII) helices. The (VG)5 repeat motif is completely disordered, and residues 200-250 adopt three partially populated α-helices. Residues 345-355, which comprise the nuclear localization signal (NLS), form a modestly populated α-helix which may mediate STAT5B binding. These findings allow us to suggest a model for nascent hCPEB3 structural transitions at single residue resolution, advancing that amyloid breaker residues, like proline, are a key difference between functional versus pathological amyloids. Our NMR spectroscopic analysis of hCPEB3 provides insights into the first structural transitions involved in protein-protein and protein-mRNA interactions. The atomic level understanding of these structural transitions involved in hCPEB3 aggregation is a key first step toward understanding memory persistence in humans, as well as sequence features that differentiate beneficial amyloids from pathological ones. Biophysics, Structural Biology, Biochemistry & Neurosciences.


Clinical utility of corpus callosum measurements in head sonograms of preterm infants: a cohort study.
To assess the clinical usefulness of measurement of corpus callosum (CC) size in head ultrasound (HUS) to predict short-term neurodevelopmental (ND) outcomes in preterm infants. We hypothesised that including CC measurements in routine HUS will be an additional tool for early identification of infants at risk of adverse short-term ND outcome, over and above the predictive power of perinatal morbidities. Retrospective cohort study. Level III neonatal intensive care unit (NICU) and outpatient NICU follow-up clinic of an academic medical centre in New York City. 929 HUS of 502 infants with gestational age of 23-36 weeks in African-American infants were initially studied. Exclusion criteria included those who died, had gross abnormalities in HUS, infants with race other than African-American, infants with suboptimal quality of HUS, late preterm infants and infants who did not participate in ND follow-up. A total of 173 infants completed the study. CC size (length and thickness) was measured in a subset of 87 infants who had routine HUS between 23 and 29 weeks (0-6 postnatal weeks). Relevant clinical variables were collected from chart reviews. ND assessments were completed in outpatient follow-up clinics. A statistical model was developed to assess the clinical utility and possible predictive value of CC measurements for adverse short-term ND outcome, while adjusting for perinatal morbidities. CC size and ND status. Measurements of CC size did not add substantial predictive power to predict short-term ND outcome beyond the information provided by the presence of morbidities related to prematurity. No association was found between morbidities related to prematurity and short-term ND outcome and CC size in preterm infants. CC measurements in HUS early in life did not have an additional value in predicting short-term ND outcome, therefore did not seem to provide further clinical utility.


Estimating Diversity Through Time Using Molecular Phylogenies: Old and Species-Poor Frog Families are the Remnants of a Diverse Past.
Estimating how the number of species in a given group varied in the deep past is of key interest to evolutionary biologists. However, current phylogenetic approaches for obtaining such estimates have limitations, such as providing unrealistic diversity estimates at the origin of the group. Here, we develop a robust probabilistic approach for estimating diversity through time curves and uncertainty around these estimates from phylogenetic data. We show with simulations that under various realistic scenarios of diversification, this approach performs better than previously proposed approaches. We also characterize the effect of tree size and undersampling on the performance of the approach. We apply our method to understand patterns of species diversity in anurans (frogs and toads). We find that Archaeobatrachia-a species-poor group of old frog clades often found in temperate regions-formerly had much higher diversity and net diversification rate, but the group declined in diversity as younger, nested clades diversified. This diversity decline seems to be linked to a decline in speciation rate rather than an increase in extinction rate. Our approach, implemented in the R package RPANDA, should be useful for evolutionary biologists interested in understanding how past diversity dynamics have shaped present-day diversity. It could also be useful in other contexts, such as for analyzing clade-clade competitive effects or the effect of species richness on phenotypic divergence.


Immunohistochemical Expression of Alpha-Methyl-Coa (AMACR) and ERG in Prostatic Adenocarcinoma and Prostatic Hyperplasia: A Comparative Study.
This observational comparative study aimed at investigating the diagnostic accuracy of ERG in differentiating benign and malignant prostatic lesions and comparing it to the diagnostic accuracy of AMACR. We also aimed at comparing AMACR and ERG expression to Gleason grade of the carcinoma cases. Seventy- two cases (22 prostatic hyperplasia and 50 prostatic carcinoma) were collected from the pathology department at Cairo university. The cases were immunostained by antibodies against AMACR and ERG. Immunohistochemical expressions of both markers were differentially examined in benign and malignant cases, compared to each other's, as well as, to the grade group of the malignant cases. AMACR showed 62% sensitivity and 86.4% specificity for the diagnosis of PC, with a statistically significant differential expression in benign and malignant lesions (P=0.001). Its expression also correlated significantly with the age (p=0.007), Gleason grade (P=0.006) and perineural invasion (P=0.011). Although ERG showed 100% specificity to PC with no expression in hyperplasia cases, it showed only 22% sensitivity for PC cases. ERG expression also showed statistically significant correlation with the Gleason grade. No association between ERG and AMACR expression was detected in our study (P=0.151). Regarding the diagnostic accuracy, although ERG accuracy was much lower than that of AMACR, combining both markers yielded a higher diagnostic accuracy. Although ERG proved no superior value than AMACR in diagnosing prostatic lesions, combining both markers may lead to higher diagnostic accuracy owing to higher ERG specificity for PC.


Comparison of complications, revisions, spinopelvic parameters, and health-related quality of life after posterior spinal fusion using multiple-rod constructs or two-rod constructs for adult spinal deformity: a systematic review and meta-analysis.
The incidence of mechanical complications is high in patients undergoing posterior spinal fusion (PSF) for adult spinal deformity (ASD), especially for cases with severe sagittal malalignment or a prior spinal fusion requiring three-column osteotomy (3-CO) or spinopelvic fixation (SPF). The purpose of this systematic review and meta-analysis was to compare the complications, revisions, radiographic spinopelvic parameters, health-related quality of life (HRQoL), and surgical data of PSF using multiple-rod constructs to those of two-rod constructs for the treatment of ASD. A comprehensive literature search was performed for relevant studies in PubMed, EMBASE, Web of Science, and the Cochrane Library. Complications, revisions, spinopelvic parameters, HRQoL, and surgical date were compared between patients with ASD who underwent PSF using multiple-rod constructs (multi-rod group) and two-rod constructs (two-rod group). Ten studies, comprising 797 patients with ASD (399 in the multi-rod group and 398 in the two-rod group), were included. All these studies were retrospective cohort studies. There were no significant differences in the surgical, wound-related, and systemic complications between the groups. In the multi-rod group, we noted a significantly lower incidence of rod fracture (RR, 0.43; 95% CI 0.33 to 0.57, P < 0.01), pseudoarthrosis (RR, 0.38; 95% CI 0.28 to 0.53, P < 0.01), and revisions (RR, 0.44; 95% CI 0.33 to 0.58, P < 0.01); a superior restoration of PI-LL (WMD, 3.96; 95% CI 1.03 to 6.88, P < 0.01) and SVA (WMD, 31.53; 95% CI 21.16 to 41.90, P < 0.01); a better improvement of ODI score (WMD, 6.82; 95% CI 2.33 to 11.31, P < 0.01), SRS-22 total score (WMD, 0.44; 95% CI 0.06 to 0.83, P = 0.02), and VAS-BP score (WMD, 1.02; 95% CI 0.31 to 1.73, P < 0.01). Compared with the two-rod constructs, PSF using multiple-rod constructs was associated with a lower incidence of mechanical complications, a lower revision rate, a superior restoration of sagittal alignment, and a better improvement of HRQoL, without increasing surgical invasiveness. Multiple-rod constructs should be routinely considered to for ASD patients, especially for cases with severe sagittal malalignment or a prior spinal fusion requiring 3-CO or SPF.


Localization of the gene for human heart fatty acid binding protein to chromosome 1p32-1p33.
Heart fatty acid binding protein (hFABP) is an abundant 14-kDa cytosolic protein thought to be involved in trafficking of fatty acids from the plasma membrane to sites of beta-oxidation in mitochondria and peroxisomes and to the endoplasmic reticulum for lipid synthesis. A human hFABP cDNA isolated by polymerase chain reaction was used as a probe for in situ hybridization to metaphase chromosomes. A fragment of the gene for human hFABP was used as a probe for fluorescence in situ hybridization to metaphase chromosomes. The cDNA and genomic probes both localized the gene for human hFABP to chromosome 1p32-1p33.


Polybrene technique for red cell antibody screening using microplates.
The manual polybrene technique was adapted as a microplate test for antibody screening to determine its sensitivity and specificity and compared with conventional tube testing using various antibodies and serologically inert sera. Equivalent results were obtained for both techniques and it is concluded that this adaptation of the polybrene technique is useful in pretransfusion testing.


Intrinsic electric fields and proton diffusion in immobilized protein membranes. Effects of electrolytes and buffers.
We present a theory for proton diffusion through an immobilized protein membrane perfused with an electrolyte and a buffer. Using a Nernst-Planck equation for each species and assuming local charge neutrality, we obtain two coupled nonlinear diffusion equations with new diffusion coefficients dependent on the concentration of all species, the diffusion constants or mobilities of the buffers and salts, the pH-derivative of the titration curves of the mobile buffer and the immobilized protein, and the derivative with respect to ionic strength of the protein titration curve. Transient time scales are locally pH-dependent because of protonation-deprotonation reactions with the fixed protein and are ionic strength-dependent because salts provide charge carriers to shield internal electric fields. Intrinsic electric fields arise proportional to the gradient of an "effective" charge concentration. The field may reverse locally if buffer concentrations are large (greater to or equal to 0.1 M) and if the diffusivity of the electrolyte species is sufficiently small. The "ideal" electrolyte case (where each species has the same diffusivity) reduces to a simple form. We apply these theoretical considerations to membranes composed of papain and bovine serum albumin (BSA) and show that intrinsic electric fields greatly enhance the mobility of protons when the ionic strength of the salts is smaller than 0.1 M. These results are consistent with experiments where pH changes are observed to depend strongly on buffer, salt, and proton concentrations in baths adjacent to the membranes.


Spatio-temporal numerical modeling of reaction-diffusion measles epidemic system.
In this work, we investigate the numerical solution of the susceptible exposed infected and recovered measles epidemic model. We also evaluate the numerical stability and the bifurcation value of the transmission parameter from susceptibility to a disease of the proposed epidemic model. The proposed method is a chaos free finite difference scheme, which also preserves the positivity of the solution of the given epidemic model.


Intragastric titration of acid in the perfused rat stomach preparation following parenteral and intraluminal stimulation.
The anaesthetised rat stomach preparation was adapted to assay intraluminally administered stimulants and inhibitors of acid secretion by continuously recirculating the perfusate (15 ml of 5% glucose) and measuring acid by the pH-stat technique. The responses obtained were linear. Continuous artificial neutralisation of the stomach to pH 5.5 as well as variation of the pH between 6.5 and 4.0 did not significantly alter the sensitivity of the preparation to intravenously administered human gastrin-heptadecapeptide I (HG I). Basal acid secretion however significantly declined following stepwise lowering of the intragastric pH between 6.5 and 4.0. The threshold values for responses to i.v. HG I were below 16 ng. 6 doses could be given per rat without tachyphylaxis. Acetylcholine, 1.3, 2.5, 5.2 and 10.4 micron g/ml in the perfusate, induced a dose-dependent linear (r=0.902) acid secretion. Metiamide 1.66 mg/ml in the perfusate, produced a parallel shift to the right of the HG I dose--response curve producing an agonist dose ratio of 3.66. The data suggest that intragastrically applied stimulants and inhibitors of acid secretion can be studied precisely in this relatively simple preparation.