Chemotherapeutic targeting of cell death pathways.
Cell death plays an important role in cancer growth and progression, as well as in the efficiency of chemotherapy. Although apoptosis is commonly regarded as the principal mechanism of programmed cell death, it has been increasingly reported that several anticancer agents do not only induce apoptosis but other forms of cell death such as necrosis, autophagy and mitotic catastrophe, as well as the state of permanent loss of proliferative capacity known as senescence. A deeper understanding of what we know about chemotherapy-induced death is rather relevant considering the emerging knowledge of non-apoptotic cell death signaling pathways, and the fact that many tumors have the apoptosis pathway seriously compromised. In this review we examine the effects that various anti-cancer agents have on pathways involved in the different cell death outcomes. Novel and specific anti-cancer agents directed toward members of the cell death signaling pathways are being developed and currently being tested in clinical trials. If we precisely activate or inhibit molecules that mediate the diversity of cell death outcomes, we might succeed in more effective and less toxic chemotherapy.


Neurodevelopmental profiles of children with unilateral cerebral palsy associated with middle cerebral artery and periventricular venous infarctions.
To compare the neurodevelopment of children with unilateral cerebral palsy (CP) with middle cerebral artery (MCA) and periventricular venous infarctions (PVIs). In this cross-sectional study, children with unilateral CP completed a neurological exam, unimanual Quality of Upper Extremity Skills Test, hand usage questionnaires, and IQ test. Neuroimaging was obtained from health records. Two hundred and forty-five participants with unilateral CP had neuroimaging (151 [61.9%] male, ages 2-18y, median=7y 6mo, interquartile range [IQR]=6y 7mo, with 93.6% in Gross Motor Function Classification System level I/II and 78.8% in Manual Ability Classification System level I/II). Ninety-seven (39.6%) had MCA injuries and 106 (43.3%) had periventricular white matter injuries, of which 48 (45.3%) were PVIs. Median Quality of Upper Extremity Skills Test for the MCA group was 49.2 (IQR=55.8), PVI 79.9 (IQR=23.6) (Mann-Whitney U=988.50, p<0.001). Bimanual hand usage (Children's Hand-use Experience Questionnaire) (Mann-Whitney U=425, p<0.001) and light touch (odds ratio=9.12, 95% confidence interval 1.28-400.76, Fisher's exact test p=0.017) were lower in the MCA compared to the PVI group. Full-scale IQ median centile score for the MCA group was 18.0 (IQR=35.5) and 50.0 (IQR=30.0) for the PVI group (Mann-Whitney U=382, p<0.001). Children with unilateral CP and MCA injuries demonstrated lower hand function and usage, decreased light touch, and lower IQs compared to the PVI group. This study aids in defining rehabilitation needs informed by brain injury patterns.


Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism.
Nerve growth factor (NGF) is well characterized for its neurotrophic actions on peripheral sensory and sympathetic neurons and on central cholinergic neurons of the basal forebrain. Recent evidence, however, has shown high levels of NGF to be present in a variety of biological fluids after inflammatory and autoimmune responses, suggesting that NGF is a mediator of immune interactions. Increased NGF serum levels have been reported in both humans and experimental animal models of psychological and physical stress, thus implicating NGF in neuroendocrine interactions as well. The possible source(s) and the regulatory mechanisms involved in the control of serum NGF levels, however, still remain to be elucidated. We now report the presence of both NGF gene transcripts and protein in the anterior pituitary. Immunofluorescence analysis indicated that hypophysial NGF is selectively localized in mammotroph cells and stored in secretory granules. NGF is cosecreted with prolactin from mammotroph cells by a neurotransmitter-dependent mechanism that can be pharmacologically regulated. Activation of the dopamine D2 receptor subtype, which physiologically controls prolactin release, resulted in a complete inhibition of vasoactive intestinal peptide-stimulated NGF secretion in vitro, whereas the specific D2 antagonist (-)-sulpiride stimulated NGF secretion in vivo, suggesting that the anterior pituitary is a possible source of circulating NGF. Given the increased NGF serum levels in stressful conditions and the newly recognized immunoregulatory function of this protein, NGF, together with prolactin, may thus be envisaged as an immunological alerting signal under neuronal control.


A finite element analysis for the prediction of load-induced fluid flow and mechanochemical transduction in bone.
Interstitial fluid flow through the lacunocanalicular cavities of mechanically loaded bone provides the biophysical basis for a number of postulates regarding mechanotransduction in bone. Recently, the existence of load-induced fluid flow and its influence on molecular transport through bone has been confirmed using tracer methods to visualize fluid flow induced by in vivo four-point-bending of rat tibiae. In this paper, we present a theoretical two-stage approach for the calculation of load-induced flow fields and for the evaluation of their influence on molecular transport in bone loaded in four-point bending, analogous to the aforementioned experimental model. In the first stage, the fluid velocities are calculated using a three-dimensional, poroelastic finite element model. In the second stage, mass transport analysis, this calculated fluid flow serves as a forced convection flow and its contribution to the total transport potential is determined. Based on this combined approach, the overall tracer concentration in the loaded bone is significantly higher than that in the unloaded bone. Furthermore, augmentation of mass transport through convective flow is more pronounced in the tension band of the tissue, as compared to the compression band. In general, augmentation of tracer concentration via convective mechanisms is most pronounced in areas corresponding to lowest fluid velocities, which is indicative of fluid flow direction and areas of increased "dwell time" or accumulation during the loading cycle. This theoretical model, in combination with the corresponding experimental model, provides unique insight into the role of mechanical loads in modulating local flow distributions and concentration gradients within bone tissue.


Diagnosing Perioperative Cardiovascular Risks in Noncardiac Surgery Patients.
Every year, over 200 million adults are undergoing noncardiac surgery. These noncardiac surgery patients may face the risk of cardiac mortality and morbidity during the perioperative and recovery periods. Around ten million patients who underwent noncardiac surgery experience cardiac complications within the first 30 days of the postoperative period; the complications are myocardial infarction, cardiac death, and cardiac arrest. This cardiovascular risk is mostly faced by the patients having cerebrovascular or cardiac disease and the patients with the age greater than 50 years. Monitoring and treating cardiac diseases with a suitable biomarker during the perioperative period is necessary for the early recovery of noncardiac surgery patients. This review discussed the risk factors and the key guidelines to avoid the cardiovascular risks during the perioperative period of noncardiac surgery patients. In addition, the biomarkers and identification strategies for cardiac diseases are discussed.


Efficacy of PBTZ169 and pretomanid against Mycobacterium avium, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum in BALB/c mice models.
We aimed to evaluate the activity of PBTZ169 and pretomanid against non-tuberculous mycobacteriosis (NTM) in vitro and in vivo. The minimum inhibitory concentrations (MICs) of 11 antibiotics, against slow-growing mycobacteria (SGMs) and rapid-growing mycobacteria (RGMs) were tested using the microplate alamarBlue assay. The in vivo activities of bedaquiline, clofazimine, moxifloxacin, rifabutin, PBTZ169 and pretomanid against four common NTMs were assessed in murine models. PBTZ169 and pretomanid had MICs of >32 μg/mL against most NTM reference and clinical strains. However, PBTZ169 was bactericidal against Mycobacterium abscessus (3.33 and 1.49 log10 CFU reductions in the lungs and spleen, respectively) and Mycobacterium chelonae (2.29 and 2.24 CFU reductions in the lungs and spleen, respectively) in mice, and bacteriostatic against Mycobacterium avium and Mycobacterium fortuitum. Pretomanid dramatically decreased the CFU counts of M. abscessus (3.12 and 2.30 log10 CFU reductions in the lungs and spleen, respectively), whereas it showed moderate inhibition of M. chelonae and M. fortuitum. Bedaquiline, clofazimine, and moxifloxacin showed good activities against four NTMs in vitro and in vivo. Rifabutin did not inhibit M. avium and M. abscessus in mice. PBTZ169 appears to be a candidate for treating four common NTM infections. Pretomanid was more active against M. abscessus, M. chelonae and M. fortuitum than against M. avium.


Activation of JNK and IRE1 is critically involved in tanshinone I-induced p62 dependent autophagy in malignant pleural mesothelioma cells: implication of p62 UBA domain.
The aim of present study is to elucidate autophagic mechanism of tanshinone I (Tan I) in H28 and H2452 mesothelioma cells. Herein, Tan I exerted cytotoxicity with autophagic features of autophagy protein 5 (ATG5)/ microtubule-associated protein 1A/1B-light chain 3II (LC3 II) activation, p62/sequestosome 1 (SQSTM1) accumulation and increased number of LC3II punctae, acridine orange-stained cells and autophagic vacuoles. However, 3-methyladenine (3MA) and NH4Cl increased cytotoxicity in Tan I treated H28 cells. Furthermore, autophagy flux was enhanced in Tan I-treated H28 cells transfected by RFP-GFP-LC3 constructs, with colocalization of GFP-LC3 punctae with LAMP1 or Lysotracker. Interestingly, C-terminal UBA domain is required for Tan 1 induced aggregation of p62 in H28 cells. Notably, Tan I upregulated CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring protein-1 (IRE1) and p-c-Jun N-terminal kinase (p-JNK), but silencing of IRE1 or p62 and JNK inhibitor SP600125 blocked the LC3II accumulation in Tan I-treated H28 cells. Overall, these findings demonstrate that Tan I exerts antitumor activity through a compromise between apoptosis and p62/SQSTM1-dependent autophagy via activation of JNK and IRE 1 in malignant mesothelioma cells.


The long-term efficacy of azathioprine in steroid-dependent ulcerative colitis.
OBJECTIVE. The long-term efficacy of azathioprine (AZA) in steroid-dependent ulcerative colitis (UC) is still unclear. We aimed to evaluate the efficacy of AZA in patients with steroid-dependent UC. MATERIAL AND METHODS. We retrospectively reviewed the medical records of 106 patients with steroid-dependent UC who were administered AZA. Three-year outcomes of AZA therapy were evaluated. The outcome of the treatment was defined as (1) success, indicating induction and maintenance of remission throughout the study period (complete success) or remission followed by infrequent and short relapses (partial success); or (2) failure, indicating the absence of remission, frequent or prolonged relapses, infliximab administration, or colectomy. RESULTS. Of the 106 patients, 73 (68.9%) continued on AZA for >6 months (AZA therapy group) and 33 (31.1%) discontinued AZA within 6 months due to intolerance (AZA intolerance group, n = 20), colectomy (n = 6), or follow-up loss (n = 7). Three-year outcomes for 106 patients were success in 54.7% (complete success, 35.8%; partial success, 18.9%), failure in 32.1% (frequent or prolonged relapses, 12.3%; infliximab administration, 5.6%; colectomy, 14.2%), and follow-up loss or death in 13.2%. The success rate increased to 71.2% (complete success, 46.6%; partial success, 24.7%) when the analysis was confined to the 73 patients who continued AZA for > 6 months. The 3-year success rate was higher in the AZA therapy group (71.2%) than the AZA intolerance group (25.0%) (p < 0.001). CONCLUSIONS. AZA is an effective treatment for steroid-dependent UC. The efficacy of AZA is well sustained over 3 years.


Extrahepatic expression of fibrinogen by granulosa cells: potential role in ovulation.
Granulosa cells from ovarian follicles were shown to express and secrete fibrinogen under the control of FSH. Conditioned medium was collected from granulosa cell cultures and found to contain FSH-dependent 50-kilodalton (kDa) and 93- to 95-kDa proteins. N-Terminal microsequence analysis identified these proteins as fibrinogen beta- and gamma-chains, respectively. Proteins migrating at 93 and 95 kDa contain identical gamma-chain sequences at the N-terminal, suggesting differential processing of fibrinogen. These fibrinogen chains were specifically detected with antifibrinogen antibodies in immunoblot and immuno-precipitation analysis. Fibrinogen gamma-chain mRNA was detected in granulosa cells by polymerase chain reaction analysis, confirming fibrinogen gene expression by these cells. Fibrinogen secretion by granulosa cells was measured by a competitive enzyme-linked immunosorbent assay. Granulosa cells treated with FSH (100 ng/ml) secreted 2-3 times more fibrinogen than untreated cells. These data show that fibrinogen, a major product of the liver, is also a secretory product of granulosa cells. This provides a novel extrahepatic site of fibrinogen expression. As hepatic parenchymal cells normally maintain high circulating levels of fibrinogen, the local production of fibrinogen in the ovary is anticipated to have specialized functions. Locally produced fibrinogen may be important in the clotting process following tissue rupture at ovulation. In addition, fibrinogen fragments may be involved in the mechanism of ovulation by increasing the activity of tissue-type plasminogen activator to control the proteolytic activity required for ovulation.


Excitatory amino acid transmitters in neuronal circuits of the cat visual cortex.
To test a possibility that glutamate (Glu) and aspartate (Asp) are transmitters in the visual cortex and to locate their operating sites in the cortical circuitry, we studied effects of microiontophoretic application of Glu/Asp antagonists on visual responses of cortical neurons in the cat. The antagonists tested were kynurenic acid (KYNA), cis-2,3-piperidine dicarboxylic acid, and gamma-D-glutamylglycine. Among these antagonists, KYNA was most effective in blocking visual responses of cortical neurons; it eliminated visual responses in 156 of the 188 cells tested. Usually the maximal suppressive effect appeared 20-30 s after starting KYNA application and recovery of cell's responsiveness 30-60 s after stopping the application. KYNA antagonized excitations induced by ionophoretic application of Glu and Asp but did not block those by acetylcholine, suggesting that KYNA is a selective antagonist of Glu/Asp, and its action is not due to general depressant effects. This suggestion was further supported by the observation that in corticogeniculate cells the latency and probability of invasion of antidromic spikes into the somatodendritic part following electrical stimulation of the lateral geniculate were not changed while visual responses were completely suppressed by KYNA. In terms of actions of the three agonists which give the basis for classifying excitatory amino acid receptors into at least three types, KYNA antagonized excitations by N-methyl-D-aspartic acid (NMDA) and kainate in almost all the cells tested but did not block those by quisqualate in about half of the cells. These results suggest that KYNA reacts more preferentially with NMDA and kainate receptors than with quisqualate receptors. Effectiveness of KYNA was related to types of receptive fields of cells and to their laminar locations. In 79 of the 104 simple cells tested, KYNA completely suppressed their visual responses, while such a complete block was seen in only 18 of the 68 complex and 3 of the 16 special complex cells. The great majority of the cells in layers IVab, IVc and the upper part of layer VI were completely suppressed by KYNA, whereas most of the cells in the other layers were incompletely suppressed or not suppressed at all.(ABSTRACT TRUNCATED AT 400 WORDS)


Revisiting B cell tolerance and autoantibodies in seropositive and seronegative autoimmune rheumatic disease (AIRD).
Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent upon the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti-citrullinated protein antibodies. Autoantibody-based diagnostics have proved helpful in patient care, not only for diagnosis but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. In this study we discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative.


The effect of mild heat stress of different frequencies on the adaptability of Drosophila melanogaster females.
In natural populations, insects regularly face an adverse impact of different natures: harsh weather swings, lack of food resources, the insecticidal treatment. We studied the effect of repeated episodes of mild heat stress of different frequencies on stress resistance of Drosophila melanogaster females. We found out that the mild heat stress (38°С, 1 hr) repeated daily within 2 weeks resulted in (a) an increased activity of the dopamine (DA) metabolism enzymes, DA-dependent arylalkylamine N-acetyltransferase and alkaline phosphatase, which suggested a decrease in DA level, and (b) an increased survival rate under acute heat stress (38°С, 4 hr). The same mild heat stress repeated weekly had no effect on these parameters.


Efficacy and complications of computed tomography-guided hook wire localization.
Video-assisted thoracic surgery offers a minimally invasive method for diagnosing and treating small pulmonary lesions, although the localization of these lesions is sometimes problematic. Various localization methods have been reported but few studies have described their efficacy and adverse events. We performed computed tomography (CT)-guided localization using a hook wire in 417 patients with 500 lesions treated between January 2006 and December 2010. We located 178 lesions with a ground-glass opacity component and 322 solid lesions. The solid lesions had smaller tumor diameters and were located further from the pleura. Tumor depth to size ratio was 0.9 ± 0.9 for the lesions with a ground-glass opacity component and 1.8 ± 1.5 for the solid lesions (p < 0.001). Pneumothorax requiring aspiration was observed in 4.6% patients, and hemoptysis and pulmonary hematoma was observed in 10.3%. Systemic air embolism with no sequelae and spontaneous resolution occurred in a patient (0.24%). The morbidity rate was 15.1%. Male patients, patients who had undergone multiple localization, and heavy smokers were at a higher risk of pneumothorax requiring aspiration. Insertion distance more than 25 mm was a risk factor for hemoptysis and pulmonary hematoma (p < 0.001). Procedure duration per lesion was 14 ± 5 minutes. Dislodgement occurred in 2 patients (0.4%). The safety, reliability, and convenience of CT-guided hook wire localization are acceptable. Localization for lesions with a ground-glass opacity component may be performed when the lesions are relatively large and shallow. Insertion distances greater than 25 mm are associated with a risk of pulmonary hematoma and hemoptysis.


Early postnatal development of contractile performance and responsiveness to Ca2+, verapamil and ryanodine in the isolated rat heart.
Contractile performance of the isolated perfused rat heart and its inotropic response to Ca2+, verapamil and ryanodine was studied in 1-, 2-, 4-, 7- and 12-day-old animals. Values of the developed force revealed two different phases: a slow decrease from day 1 to day 4 followed by a steep increase up to day 12. A similar biphasic time course was observed in the magnitude of the inotropic effect of Ca2+ (0.6-10.0 mmol.l-1): decrease from day 1 to day 4 followed by an increase up to day 7. The sensitivity to Ca2+ was, however, not changed. An analogous biphasic response was also observed during perfusion with the calcium antagonist verapamil (10(-9) to 3.3 x 10(-7) mol.l-1): the sensitivity to negative inotropic effect rose from day 1 to day 4 and then decreased at day 7 (values of IC50 were 170 +/- 61, 17 +/- 6 and 171 +/- 60 10(-9) mol.l-1 S.E.M. on day 1, 4 and 7, respectively). The contractile response to the inhibitor of calcium release from sarcoplasmic reticulum (SR)--ryanodine (10(-6) mol.l-1)--was surprisingly high already in 1-day-old animals (inhibition of contraction by more than 50%) indicating the presence of functionally active SR in the rat heart just after birth. Our data clearly shows that the early development of contractile function and inotropic responsiveness of the rat heart is not linear and changes dramatically during the first week of life.


Monoclonal Antibody Combinations Prevent Serotype A and Serotype B Inhalational Botulism in a Guinea Pig Model.
Botulinum neurotoxins (BoNT) are some of the most toxic proteins known, with a human LD50 of ~1 ng/kg. Equine antitoxin has a half-life in circulation of less than 1 day and is limited to a treatment rather than a prevention indication. The development of monoclonal antibodies (mAbs) may represent an alternative therapeutic option that can be produced at high quantities and of high quality and with half-lives of >10 days. Two different three mAb combinations are being developed that specifically neutralize BoNT serotypes A (BoNT/A) and B (BoNT/B). We investigated the pharmacokinetics of the anti-BoNT/A and anti-BoNT/B antibodies in guinea pigs (Cavia porcellus) and their ability to protect guinea pigs against an aerosol challenge of BoNT/A1 or BoNT/B1. Each antibody exhibited dose-dependent exposure and reached maximum circulating concentrations within 48 h post intraperitoneal or intramuscular injection. A single intramuscular dose of the three mAb combination protected guinea pigs against an aerosol challenge dose of 93 LD50 of BoNT/A1 and 116 LD50 of BoNT/B1 at 48 h post antibody administration. These mAbs are effective in preventing botulism after an aerosol challenge of BoNT/A1 and BoNT/B1 and may represent an alternative to vaccination to prevent type A or B botulism in those at risk of BoNT exposure.


Variable Rigidity Module with a Flexible Thermoelectric Device for Bidirectional Temperature Control.
Dynamic stiffness tuning is a promising approach for shape reconfigurable systems that must adapt their flexibility in response to changing operational requirements. Among stiffness tuning technologies, phase change materials are particularly promising because they are size scalable and can be powered using portable electronics. However, the long transition time required for phase change is a great limitation for most applications. In this study, we address this by introducing a rapidly responsive variable rigidity module with a low melting point material and flexible thermoelectric device (f-TED). The f-TED can conduct bidirectional temperature control; thereby, both heating and cooling were accomplished in a single device. By performing local cooling, the phase transition time from liquid to solid is reduced by 77%. The module in its rigid state shows 14.7 × higher bending stiffness than in the soft state. The results can contribute to greatly widening the application of phase transition materials for variable rigidity.


A practical algorithm for finding maximal exact matches in large sequence datasets using sparse suffix arrays.
High-throughput sequencing technologies place ever increasing demands on existing algorithms for sequence analysis. Algorithms for computing maximal exact matches (MEMs) between sequences appear in two contexts where high-throughput sequencing will vastly increase the volume of sequence data: (i) seeding alignments of high-throughput reads for genome assembly and (ii) designating anchor points for genome-genome comparisons. We introduce a new algorithm for finding MEMs. The algorithm leverages a sparse suffix array (SA), a text index that stores every K-th position of the text. In contrast to a full text index that stores every position of the text, a sparse SA occupies much less memory. Even though we use a sparse index, the output of our algorithm is the same as a full text index algorithm as long as the space between the indexed suffixes is not greater than a minimum length of a MEM. By relying on partial matches and additional text scanning between indexed positions, the algorithm trades memory for extra computation. The reduced memory usage makes it possible to determine MEMs between significantly longer sequences. Source code for the algorithm is available under a BSD open source license at http://compbio.cs.princeton.edu/mems. The implementation can serve as a drop-in replacement for the MEMs algorithm in MUMmer 3.


Detection of bone metastases using diffusion weighted magnetic resonance imaging: comparison with (11)C-methionine PET and bone scintigraphy.
We evaluated the ability of diffusion-weighted imaging (DWI) to detect bone metastasis by comparing the results obtained using this modality with those obtained using (11)C-methionine (MET) positron emission tomography (PET) and bone scintigraphy. This retrospective study involved 29 patients with bone metastasis. DWI was obtained using a single-shot echo planar imaging (EPI) sequence with fat suppression using a short inversion time inversion recovery sequence. The detection capabilities of DWI for bone metastases were compared with those of whole body MET PET (in 19 patients) and 99mTc-methylene diphosphonate bone scintigraphy (in 15 patients). Among the 19 patients who were diagnosed using DWI and PET, the PET identified 39 bone metastases, while the DWI identified 60 metastases out of 69 metastases revealed with conventional magnetic resonance imaging (MRI). Among the 15 patients who were diagnosed using DWI and bone scintigraphy, the bone scintigraphy identified 18 bone metastases, while the DWI identified 72 metastases out of 78 metastases revealed with conventional MRI. The overall bone metastasis detection rates were 56.5% for PET, 23.1% for bone scintigraphy and 92.3% for DWI. DWI is a very sensitive method for detecting bone metastasis and is superior to MET PET and bone scintigraphy in terms of its detection capabilities.


GABAergic inhibition shapes frequency adaptation of cortical activity in a frequency-dependent manner.
Primary sensory cortical areas continuously receive thalamic inputs that arrive at different frequencies depending on the amount of sensory activity. The cortical response to repeated sensory stimuli rapidly adapts and different frequencies recruit cortical neuronal networks to different extents. GABAergic inhibition limits the spread of excitation within cortical neuronal networks. However, it is unknown how frequency adaptation of cortical network activity at different frequencies is shaped by GABAergic inhibition. Here, we find that in acute slices of visual cortex area V1 GABAergic inhibition affects frequency adaptation depending on the frequency of activity. Using voltage-sensitive dye imaging, we found that while increasing inhibitory postsynaptic currents (IPSCs) with flunitrazepam dampened the spread of cortical excitation, short-term adaptations to different stimulation frequencies were differentially affected. At high frequencies (40 Hz), facilitation of cortical excitation was no longer transient, but facilitation was sustained. At low frequencies (10 Hz) flunitrazepam decreased a depression of the excitation. In contrast, in mice lacking the GABA(A) receptor alpha1 subunit facilitation was reduced and depression enhanced. These findings suggest that GABAergic inhibition affects cortical excitation at different frequencies differentially, favoring facilitation at higher frequencies of excitation.


Periodontal diseases in an Omani adult population: a preliminary study.
Data on the periodontal status of the adult population in the Arab world are scarce. The aim of this pilot study is to assess the prevalence, extent, and severity of periodontal diseases in an adult group from Oman. This is a cross-sectional study of 319 teachers who were randomly sampled from the list of teachers from the Muscat region schools in Oman. Dental caries, tooth loss, and periodontal attachment loss (AL) were recorded for each of the participants. A questionnaire collected data on participants' sociodemographic characteristics, dental-care characteristics, self-rated periodontal status, and self-rated well-being. A total of 99% of participants had at least one site with probing depth (PD) or clinical AL of ≥ 3 mm. More than one third (36%) of participants had at least one site with AL ≥ 5 mm, and 12% had at least one site with AL ≥ 6 mm; for PD, the prevalence estimates were 26% and 8%, respectively, and a gradient by age group was evident across the different thresholds. Regarding the extent of disease, 17.6% of sites had PD ≥ 3 mm, and 21% of sites had AL ≥ 3 mm. The prevalence, extent, and severity of periodontitis were higher than estimates reported from industrialized countries, such as Australia, New Zealand, and the United States. This is of concern, especially when considering the relatively young age of the study population. Because of this high prevalence, investigation of periodontitis in a national sample of Omanis is desirable to confirm the findings of this study.


Pharmacokinetic variability of beta-lactams in critically ill patients: A narrative review.
The use of antibacterial drugs is very common in critically ill patients and beta-lactam agents are widely used in this context. Critically ill patients show several characteristics (e.g., sepsis, renal impairment or conversely augmented renal clearance, renal replacement therapy) that may alter beta-lactam pharmacokinetics (PK) in comparison with non-critically ill patients. This narrative literature review aims to identify recent studies quantifying the variability of beta-lactams volume of distribution and clearance and to determine its main determinants. Seventy studies published between 2000 and 2018 were retained. Data on volume of distribution and clearance variability were reported for 5 penicillins, 3 beta-lactamase inhibitors, 6 cephalosporins and 4 carbapenems. Data confirm specific changes in PK parameters and important variability of beta-lactam PK in critically ill patients. Renal function, body weight and use of renal replacement therapy are the principal factors influencing PK parameters described in this population. Few studies have directly compared beta-lactam PK in critically ill versus non-critically ill patients. Conclusions are also limited by small study size and sparse PK data in several studies. These results suggest approaches to assess this PK variability in clinical practice. Beta-lactam therapeutic drug monitoring seems to be the best way to deal with this issue.


Mercury, Lead, and Cadmium in the Muscles of Five Fish Species from the Mechraâ-Hammadi Dam in Morocco and Health Risks for Their Consumers.
This study aims to assess the degree of metal contamination (mercury (Hg), cadmium (Cd), and lead (Pb)) in the muscles of five species of fish Esox lucius, Sander lucioperca, Micropterus salmoides, Lepomis macrochirus, and Scardinius erythrophthalmus, from the Mechraâ-Hammadi Dam between July 2017 and May 2018, and to conduct a risk assessment for human consumers. Trace metals were determined by Graphite Furnace Atomic Absorption Spectrometry for the Pb and the Cd and by Cold Vapor Atomic Absorption Spectrometry for the Hg. The results gotten from the study of the muscles of the different fish species show that the higher mean amounts of Cd and Hg were determined in E. lucius, and the maximum mean levels of Pb were detected in S. erythrophthalmus. Results suggested that demersal fishes inhabiting near the sediments and piscivorous fishes with higher trophic level were likely to accumulate higher trace metal concentrations. The general order of bioaccumulation of the trace metals measured in the muscles of the fish species is as follows: Hg > Pb > Cd. Therefore, the bioaccumulation of Hg in fish studied is more important than that of Cd and Pb. Furthermore, these concentrations are higher in summer than in winter for all trace metals. All the values of the trace metals in the muscle tissues are below the maximum limits recommended by the European Community (EC) N° 1881/2006. However, estimation of noncarcinogenic health risks by the target hazard quotient indicated no obvious noncarcinogenic risks to humans that consume those fishes (THQ < 1). Results of THQ and maximum safe consumption indicated that Hg may cause more harm to human by fish consumption especially for E. lucius and S. lucioperca. Therefore, reduced intake of carnivorous fishes should be promoted as part of a healthier diet.


Risk profile of subcutaneous port placement in small children.
Long-term central venous access is a safe and common procedure in children. However, complications with devices are a reality. Smaller children are thought to have a higher rate of complication after port placement, and some surgeons avoid placing ports with an arbitrary weight cutoff out of concern for surgical site morbidity. We performed a multi-institutional retrospective review of 500 patients less than 5 years of age undergoing port placement at three large volume children's hospitals from 2014 to 2018. Patients were divided by weight greater than or less than 10 kg at the time of insertion. Statistical analysis was performed to evaluate for differences in outcomes between the two groups. The majority of ports were placed for chemotherapy access (71.8%). Other indications included long-term infusions (18.8%) and difficult chronic IV access (9.4%). Of the 500 charts reviewed, 110 (22%) experienced some documented complication (28.9% <10 kg, 20.6% >10 kg, p = 0.096). There were no differences between the two groups in terms of the type or timing of complications. Overall, 16.3% of ports required removal prior to the end of therapy owing to a complication. Complication rate per day with the port in place was not different between the two groups (<10 kg: 0.68 complications/1000 port-days vs >10 kg 0.44 complications/1000 port-days, p = 0.068). Weight less than 10 kg was not associated with a significantly higher incidence of any type of port complication in our cohort. This suggests that concern for complications should not exclude children less than 10 kg from port placement. Multi-institutional retrospective review. Level III.


In vitro comparison of novel polyurethane aortic valves and homografts after seeding and conditioning.
The aim of the study was to compare the behavior of seeded cells on synthetic and natural aortic valve scaffolds during a low-flow conditioning period. Polyurethane (group A) and aortic homograft valves (group B) were consecutively seeded with human fibroblasts (FB), and endothelial cells (EC) using a rotating seeding device. Each seeding procedure was followed by an exposure to low pulsatile flow in a dynamic bioreactor for 5 days. For further analysis, samples were taken before and after conditioning. Scanning electron microscopy showed confluent cell layers in both groups. Immunohistochemical analysis showed the presence of EC and FB before and after conditioning as well as the establishment of an extracellular matrix (ECM) during conditioning. A higher expression of ECM was observed on the scaffolds' inner surface. Real-time polymerase chain reaction showed higher inflammatory response during the conditioning of homografts. Endothelialization caused a decrease in inflammatory gene expression. The efficient colonization, the establishment of an ECM, and the comparable inflammatory cell reaction to the scaffolds in both groups proved the biocompatibility of the synthetic scaffold. The newly developed bioreactor permits conditioning and cell adaption to shear stress. Therefore, polyurethane valve scaffolds may offer a new option for aortic valve replacement.


Presence of low virulence chytrid fungi could protect European amphibians from more deadly strains.
Wildlife diseases are contributing to the current Earth's sixth mass extinction; one disease, chytridiomycosis, has caused mass amphibian die-offs. While global spread of a hypervirulent lineage of the fungus Batrachochytrium dendrobatidis (BdGPL) causes unprecedented loss of vertebrate diversity by decimating amphibian populations, its impact on amphibian communities is highly variable across regions. Here, we combine field data with in vitro and in vivo trials that demonstrate the presence of a markedly diverse variety of low virulence isolates of BdGPL in northern European amphibian communities. Pre-exposure to some of these low virulence isolates protects against disease following subsequent exposure to highly virulent BdGPL in midwife toads (Alytes obstetricans) and alters infection dynamics of its sister species B. salamandrivorans in newts (Triturus marmoratus), but not in salamanders (Salamandra salamandra). The key role of pathogen virulence in the complex host-pathogen-environment interaction supports efforts to limit pathogen pollution in a globalized world.


Photocatalytic degradation of pesticide methomyl: determination of the reaction pathway and identification of intermediate products.
The degradation of pesticide methomyl in aqueous solution by UV-irradiation in the presence of TiO2 "Degussa P-25" has been studied. It was found that mineralisation to carbon dioxide, water, sulfate and ammonia took place during the process. The rate of photodecomposition of methomyl was measured using high performance liquid chromatography (HPLC), while its mineralization was followed using ion chromatography (IC), and total organic carbon (TOC) analysis. The identification of reaction intermediate products was carried out using coupled techniques HPLC-MS (electrospray ionization in positive mode) and a degradation pathway was proposed. Under our conditions, complete disappearance of 1.23 x 10(-4) mol l(-1) of pure pesticide occurred within 45 min of illumination and 80% TOC removal occurred in less than 4 h. Three main intermediates were identified resulting from (i) the rupture of the ester bond (or the N-O bond), (ii) the hydroxylation of methyl group borne by the nitrogen atom and (iii) the product resulting from the decarboxylation of the oxidized hydroxylated methyl group (photo-Kolbe reaction). In order to be sure that the photocatalytic results were consistent, hydrolysis and photolysis tests were performed. Photocatalysis proved to be an excellent new advanced oxidation technology (AOT) to eliminate methomyl present in water.


Prediction of protein-binding residues: dichotomy of sequence-based methods developed using structured complexes versus disordered proteins.
There are over 30 sequence-based predictors of the protein-binding residues (PBRs). They use either structure-annotated or disorder-annotated training datasets, potentially creating a dichotomy where the structure-/disorder-specific models may not be able to cross-over to accurately predict the other type. Moreover, the structure-trained predictors were shown to substantially cross-predict PBRs among residues that interact with non-protein partners (nucleic acids and small ligands). We address these issues by performing first-of-its-kind comparative study of a representative collection of disorder- and structure-trained predictors using a comprehensive benchmark set with the structure- and disorder-derived annotations of PBRs (to analyze the cross-over) and the protein-, nucleic acid- and small ligand-binding proteins (to study the cross-predictions). Three predictors provide accurate results: SCRIBER, ANCHOR and disoRDPbind. Some of the structure-trained methods make accurate predictions on the structure-annotated proteins. Similarly, the disorder-trained predictors predict well on the disorder-annotated proteins. However, the considered predictors generally fail to cross-over, with the exception of SCRIBER. Our study also reveals that virtually all methods substantially cross-predict PBRs, except for SCRIBER for the structure-annotated proteins and disoRDPbind for the disorder-annotated proteins. We formulate a novel hybrid predictor, hybridPBRpred, that combines results produced by disoRDPbind and SCRIBER to accurately predict disorder- and structure-annotated PBRs. HybridPBRpred generates accurate results that cross-over structure- and disorder-annotated proteins and produces relatively low amount of cross-predictions, offering an accurate alternative to predict PBRs. HybridPBRpred webserver, benchmark dataset and supplementary information are available at http://biomine.cs.vcu.edu/servers/hybridPBRpred/. Supplementary data are available at Bioinformatics online.


Quantal transmitter release at snake twitch and tonic muscle fibres during prolonged nerve terminal depolarization.
1. Miniature endplate currents (MEPCs) were recorded in vitro from voltage-clamped twitch and tonic muscle fibres in costocutaneous muscles of the garter snake, Thamnophis. Recordings were made from fibres in a control sodium-containing solution and then during exposure to an isotonic potassium solution containing either 1.0 mM calcium and 4.2 mM magnesium or 3.6 mM calcium. The experiments were done at two levels of external calcium in order to demonstrate that the change in MEPC frequency was calcium dependent. During the initial exposure to the isotonic potassium solutions, the MEPC frequency was increased manyfold at both twitch and tonic fibres, but it declined progressively with continued exposure. MEPCs were recorded from both fibre types throughout a 20 h exposure to the isotonic potassium solution with 1 mM calcium, but no MEPCs were recorded at most twitch endplates after approximately 6 h in the isotonic potassium solution containing 3.6 mM calcium. In contrast, MEPCs were still present at tonic fibre endplates after 20 h in the isotonic potassium solution containing 3.6 mM calcium. 2. After 30 min in the isotonic potassium solution with 1 mM calcium, the MEPC amplitude recorded from both fibre types was approximately twice that in the control sodium-containing solution. At tonic endplates, the MEPC amplitude was also twofold greater in the isotonic potassium solution with 3.6 mM calcium than in sodium-containing solution. In contrast, after 30 min in the isotonic potassium solution containing 3.6 mM calcium, the MEPC amplitude at twitch endplates was similar to that in control solution. 3. In both fibre types, MEPC amplitude decreased progressively with continued exposure to the isotonic potassium solutions. The progressive decrease in MEPC amplitude was not due to a gradual decrease in postsynaptic sensitivity to acetylcholine. 4. The effects of high potassium were reversible as MEPCs were recorded at twitch fibre endplates in preparations which were returned to the control sodium-containing solution after a 20 h exposure to the isotonic potassium solution containing 3.6 mM calcium. 5. Ultrastructural examination showed that after a 6 h exposure to the isotonic potassium solutions most nerve terminals innervating twitch fibre endplates were devoid of synaptic vesicles whereas at the same time many synaptic vesicles were present in nerve terminals innervating tonic fibre endplates. Surprisingly, numerous synaptic vesicles were present in nerve terminals innervating either fibre type in muscle preparations exposed to the isotonic potassium solutions for 20 h.(ABSTRACT TRUNCATED AT 400 WORDS)


Six1 promotes colorectal cancer growth and metastasis by stimulating angiogenesis and recruiting tumor-associated macrophages.
The homeoprotein Six1 is overexpressed in many human cancers and is associated with increased tumor progression and metastasis. Recent studies have shown that Six1 is associated with poorer overall survival in advanced-stage colorectal cancer (CRC). In the current study, we explored the functional changes and molecular events associated with Six1 overexpression in a mouse model of CRC. An orthotopic model and a splenic injection metastasis model were used to investigate the role of Six1 in CRC tumor growth and metastasis using mouse colon adenocarcinoma MC38 cells overexpressing Six1. We found that overexpression of Six1 dramatically promotes CRC tumor growth and metastasis in vivo. Six1 overexpression in MC38 increased protein levels of aldehyde dehydrogenase-1 and expanded CD44+/CD166+ populations, indicating Six1 increased features of cancer stem cells. In addition, Six1 overexpression stimulated angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). Six1-overexpressing tumor cells recruited tumor-associated macrophages (TAM) by increasing the expression of macrophage-specific colony stimulating factor, chemokine (C-C motif) ligand 2/5 and VEGF, further facilitating CRC tumor growth and metastasis. Furthermore, we determined that Six1 activated mitogen-activated protein kinase (MAPK) signaling in CRC cells. In summary, our studies strongly suggest that Six1 overexpression promotes CRC growth and metastasis and remodels tumor stroma by stimulating angiogenesis and recruiting TAM. MAPK activation may be a pivotal event in Six1-associated tumor progression, which may provide opportunities for pharmacologic intervention.


The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila.
The Polycomb (Pc) gene of Drosophila melanogaster is a member of a large class of genes (Pc group) required for the segment-specific repression of homeotic selector genes. Mutations in Pc-group genes show strong posterior transformations in homozygous embryos resulting from an ectopic expression of homeotic genes in segments where they are not supposed to be active. Genetic evidence suggests that Pc is part of a cellular memory mechanism responsible for the transmission of the homeotic expression pattern through developmental time. We have determined the nucleotide sequence for the genomic DNA of the Pc gene and for cDNAs corresponding to the 2.5-kilobase Pc mRNA. The deduced sequence of the Pc protein exhibits a homology to the heterochromatin-associated protein HP1 encoded by the suppressor of position effect variegation gene Su(var) 205. The homology is confined to a 37-amino acid domain in the N-terminal part of the two proteins. Our findings extend to the molecule level the genetically identified parallels between the Pc-group genes and the modifiers of position effect variegation. This suggests that Pc could use analogous mechanisms at the level of the higher order chromatin structure for the stable transmission of a determined state, as has been proposed for the clonal propagation of heterochromatin domains.


Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein: techniques and its significance.
Preservation of the spleen in distal pancreatectomy has recently attracted considerable attention. Since our first trial and success with spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for tumors of the pancreas and chronic pancreatitis, this procedure (Kimura's procedure) has been performed very frequently. The techniques for spleen-preserving distal pancreatectomy (SpDP) with conservation of the splenic artery and vein are clarified. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane (fusion fascia of Toldt). The connective tissue membrane is cut longitudinally above the splenic vein. It is important to remove the splenic vein from the pancreas by working from the body of the pancreas toward the spleen (median approach), because it is very difficult to remove it in the other direction. The pancreas is removed from the splenic artery by proceeding from the spleen toward the head of the pancreas. Preservation of the spleen offers various advantages. The maximum platelet levels in blood serum are significantly lower in postoperative patients with splenic preservation than in those with splenectomy. The platelet count was maximal on postoperative day 10 in the 16 patients with SpDP and the count was maximal on postoperative day 13 in the 16 patients with distal pancreatectomy with splenectomy (DPS), and there was a smaller increase in the patients with SpDP than in the patients with DPS. Postoperative bleeding from an ablated splenic artery and vein in SpDP has not been encountered. Either DPS or spleen preservation without preservation of the splenic artery and vein may reduce the blood supply to the residual proximal stomach after distal gastrectomy, which is different from the findings in the Kimura procedure. In SpDP, a very slight elevation of the platelet count in serum may help to prevent infarction of the lungs and brain compared to DPS. Another advantage of SpDP performed according to our procedure is that the blood supply to the proximal stomach is conserved in patients with SpDP who undergo distal gastrectomy with resection of the left gastric artery. Benign lesions, as well as low-grade malignancy of the body and tail of the pancreas, may be indications for this procedure. Surgeons should know the techniques and significance of SpDP with conservation of the splenic artery and vein, which is a very safe and reliable method.


Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways.
Tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are apoptosis-inducing ligands that stimulate death receptors. In this study, we investigated the effects of bufotalin, a major compound in toad venom, on sensitizing TNF-α and TRAIL-induced apoptosis of HeLa cells. Bufotalin promoted death receptor-mediated cell death, especially TRAIL-induced apoptosis, through activation of caspase-3 and PARP-1. Mitochondrial Bid-dependent pathway was activated in TNF-α-induced cell death. Cotreatment of bufotalin with TRAIL resulted in the downregulation of anti-apoptotic proteins, including Bcl-XL, Mcl-1, survivin and XIAP, and the up-regulation of MAPKs and TRAIL receptor DR5. In addition, phosphorylation of STAT1 was strongly inhibited by bufotalin. Moreover, DR5 expression was induced by knocking down the STAT1 expression. Moreover, the TRAIL-induced apoptotic response was promoted by STAT1 siRNA. Our results demonstrated that bufotalin is a powerful sensitizer of death receptor-induced apoptosis in cancer cells.


[Present possibilities of improving the diagnosis of glomerular erythrocyturia].
Examination of glomerular erythrocyturia which proved useful in the differential diagnosis of haematuria faces in practice two serious problems--the necessity to examine fresh urine and differences as regards the interpretation of criteria of glomerular erythrocyturia (from 10 to 80%). The authors examined therefore the morphology of erythrocytes in urine of 65 children with different causes of haematuria, incl. 35 patients with different forms of glomerulonephritis. They found that adding 25 mg thimerasol to 10 ml urine preserves urinary elements, incl. morphologically altered red cells for a period of 72 hours or longer. This makes it possible to examine the red cells under a phase microscope after dealing with ambulatory patients. Among various morphological forms of red cells in urine of 31 patients with glomerulonephritis in urine acanthocytes were found in a concentration above 5%, and in the majority above 20%. Acanthocyturia above 5% was not present only in 4 patients with glomerulonephritis, whereby all four suffered from mild erythrocyturia. The authors consider therefore acanthocyturia above 5% as the most reliable evidence of glomerulonephritis, in case of erythrocyturia above 10 Ery in the visual field. The criteria of acanthocyturia in children are thus lower than in adults.


Category variability effect in category learning with auditory stimuli.
The category variability effect refers to that people tend to classify the midpoint item between two categories as the category more variable. This effect is regarded as evidence against the exemplar model, such as GCM (Generalized Context Model) and favoring the rule model, such as GRT (i.e., the decision bound model). Although this effect has been found in conceptual category learning, it is not often observed in perceptual category learning. To figure out why the category variability effect is seldom reported in the past studies, we propose two hypotheses. First, due to sequence effect, the midpoint item would be classified as different categories, when following different items. When we combine these inconsistent responses for the midpoint item, no category variability effect occurs. Second, instead of the combination of sequence effect in different categorization conditions, the combination of different categorization strategies conceals the category variability effect. One experiment is conducted with single tones of different frequencies as stimuli. The collected data reveal sequence effect. However, the modeling results with the MAC model and the decision bound model support that the existence of individual differences is the reason for why no category variability effect occurs. Three groups are identified by their categorization strategy. Group 1 is rule user, placing the category boundary close to the low-variability category, hence inducing category variability effect. Group 2 takes the MAC strategy and classifies the midpoint item as different categories, depending on its preceding item. Group 3 classifies the midpoint item as the low-variability category, which is consistent with the prediction of the decision bound model as well as GCM. Nonetheless, our conclusion is that category variability effect can be found in perceptual category learning, but might be concealed by the averaged data.


Bringing to Light the Risk of Colorectal Cancer in Inflammatory Bowel Disease: Mucosal Glycosylation as a Key Player.
Colitis-associated cancer is a major complication of inflammatory bowel disease remaining an important clinical challenge in terms of diagnosis, screening, and prognosis. Inflammation is a driving factor both in inflammatory bowel disease and cancer, but the mechanism underlying the transition from colon inflammation to cancer remains to be defined. Dysregulation of mucosal glycosylation has been described as a key regulatory mechanism associated both with colon inflammation and colorectal cancer development. In this review, we discuss the major molecular mechanisms of colitis-associated cancer pathogenesis, highlighting the role of glycans expressed at gut epithelial cells, at lamina propria T cells, and in serum proteins in the regulation of intestinal inflammation and its progression to colon cancer, further discussing its potential clinical and therapeutic applications.


Building a statewide clinical trials network for cancer care in West Virginia.
In the United States, mortality rates have been declining for certain tumors, For the majority of advanced stage cancer types, cure is unattainable but treatment is still evolving. Advances in the treatment of cancer can be achieved by enrolling patients in cancer clinical trials. Presently, less than 3% of adult cancer patients participate on clinical trials in the United States. Providing cancer care and access to clinical trials are a challenge in a rural state, with a dispersed population base, such as West Virginia. Building upon recognition of barriers to clinical trials awareness and access, oncology leaders in the state are in the formative stages of developing a statewide cancer clinical trials network. Realization of this network will have an enormous impact on cancer care in our state and perhaps can serve as a model for other community and physician teams for other diseases.


Effects of nutrition on brain development in humans.
Brain development in humans is remarkably resistant to permanent damage from protein-energy malnutrition. However, specific nutrients have crucial roles. Iodine deficiency is the most important and widespread nutrient deficiency; it causes endemic cretinism, associated with deaf-mutism and cerebral palsy. Iodine deficiency during pregnancy causes both maternal and fetal hypothyroxinemia, resulting in irreversible impairment of brain development at a critical stage. Neuropathological data place this after 14 wk, perhaps continuing through the third trimester. Gross brain structure, including the gyral pattern of the cerebral cortex, develops normally; the insult affects neuron and dendrite growth. Recent magnetic-resonance-imaging (MRI) images of neurological cretin brains show remarkably normal appearance except for gliotic lesions of the globus pallidus, correlating with the proximal motor rigidity seen clinically. Myxedematous cretinism is paradoxical in showing more severe hypothyroidism and growth failure, yet better intellectual, motor, and hearing function; these observations implicate a second independent factor in its pathogenesis.


Solution Combustion Synthesis of Nanoscale Materials.
Solution combustion is an exciting phenomenon, which involves propagation of self-sustained exothermic reactions along an aqueous or sol-gel media. This process allows for the synthesis of a variety of nanoscale materials, including oxides, metals, alloys, and sulfides. This Review focuses on the analysis of new approaches and results in the field of solution combustion synthesis (SCS) obtained during recent years. Thermodynamics and kinetics of reactive solutions used in different chemical routes are considered, and the role of process parameters is discussed, emphasizing the chemical mechanisms that are responsible for rapid self-sustained combustion reactions. The basic principles for controlling the composition, structure, and nanostructure of SCS products, and routes to regulate the size and morphology of the nanoscale materials are also reviewed. Recently developed systems that lead to the formation of novel materials and unique structures (e.g., thin films and two-dimensional crystals) with unusual properties are outlined. To demonstrate the versatility of the approach, several application categories of SCS produced materials, such as for energy conversion and storage, optical devices, catalysts, and various important nanoceramics (e.g., bio-, electro-, magnetic), are discussed.


Eps8 regulates cellular proliferation and migration of breast cancer.
The role of Eps8 in human breast cancer was studied, and we found that Eps8 was overexpressed in >60% of human breast cancer samples compared with adjacent normal breast tissues by immunohistochemical analysis. Eps8 was highly expressed in the highly invasive breast cancer cell line MDA-MB‑231 compared with the weakly invasive breast cancer cell lines MCF7 and MDA-MB‑468. MCF7 cell line stably expressing Eps8 was established by G418 screening, and the ectopic expression of Eps8 enhanced MCF7 breast cancer cell growth and survival as assessed by MTT analysis, cell viability and liquid colony formation, whereas the lentiviral expression of Eps8 shRNA in MDA-MB‑231 cells resulted in a significant reduction in cellular growth and proliferation in vitro and in vivo. Furthermore, Eps8 knockdown inhibited breast cancer cell migration in wound healing assays, decreased the number and size of EGF-induced filopodia and increased the sensitivity of breast cancer cells to cisplatin analyzed by MTT assays. Eps8 knockdown decreased the levels of phosphorylated extracellular signal-regulated protein kinase (ERK) and MMP9 but increased p53. Moreover, Eps8 knockdown suppressed a partial EMT-like transition and showed a significant increase in E-cadherin and decrease in N-cadherin and vimentin. These results suggest that Eps8 is overexpressed in human breast cancers, possibly by regulating ERK signaling, MMP9, p53 and EMT-like transition to affect breast cancer cell growth, migration and invasion. Therefore, Eps8 might represent a novel potential target in human breast cancer therapy.


[Placental infection in Rwanda: comparison an HIV infected population and a control population].
We report an histological study from term placentas of 286 HIV positive women born in Rwanda. We observed chorioamnionitis without any pathogen in 15% of the cases, cocci Gram positive infection in 12 observations and malaria infection in 75% of placentas. We noted 71 cases of active malaria infection with Plasmodium falciparum trophozoites in the erythrocytes of the intervillous spaces, and 135 cases of chronic infection with malaria pigment without any parasite. An ultrastructural study performed in 8 cases of active malaria infection showed characteristic features of trophozoites and schizontes, and malaria pigment. No viral particle were seen. We did not observe any significative difference concerning the incidence of chorioamnionitis and of malaria infection in 275 HIV negative placentas. In the literature as well as in the present study, the main lesions observed in the placentas of AIDS patients were chorioamnionitis. Opportunistic infections and neoplasias of the placenta are exceptional. Detection of HIV proteins by immunochemistry or in situ hybridization is possible, but the HIV could not be identified in the trophoblast by electron microscopy. Mechanisms of the materno-fetal transmission for HIV are currently unknown.


Identification of four novel mutations in the COL4A5 gene of patients with Alport syndrome.
The type IV collagen alpha 5 chain (COL4A5) genes of patients with Alport syndrome were tested for major gene rearrangements by Southern blot analysis, using COL4A5 cDNA clones as probes. In addition, individual exons were screened for small mutations by single-strand conformation polymorphism (SSCP) analysis. Four new COL4A5 mutations were detected. A duplication of the nine most 3' located nucleotides of exon 49 and the first nucleotide of intron 49 was identified in the COL4A5 gene of one patient. Two patients displayed single base substitutions leading to, respectively, a proline to threonine and an arginine to glutamine substitution in the C-terminal end. Both substitutions involve amino acids conserved through evolution. In COL4A5 intron 41 a mutation changing the splice acceptor site from AG to AA was identified. All mutations cosegregate with the clinical phenotype of Alport syndrome in affected family members. In a control population of 50 individuals tested by PCR-SSCP these mutations were never identified. Together with two mutations reported previously, a total of six mutations were found in 26 patients with Alport syndrome (23%) after systematic screening of about 30% of the COL4A5 coding region. The clinical features of these six patients are described in detail.


Comparison of Clinical Features and Outcomes in Patients With Bilateral Versus Unilateral Adrenal Neuroblastoma.
While nearly half of cases of neuroblastoma arise in one of the adrenal glands, bilateral origin is rare. We aimed to compare clinical characteristics and outcomes between patients with bilateral versus unilateral adrenal neuroblastoma. We utilized the Surveillance, Epidemiology, and End Results database to identify patients with bilateral and unilateral adrenal neuroblastoma from 1973 to 2012. We used Fisher exact tests to compare demographics and clinical features between groups. We used Kaplan-Meier methods to describe the 5-year overall survival rate for these 2 groups. We conducted a literature review to complement the Surveillance, Epidemiology, and End Results data. Of 1617 patients in the cohort, 1585 (98%) had unilateral disease and 32 (2%) had bilateral disease. Compared with patients with unilateral disease, a significantly greater proportion of patients with bilateral disease was below 1 year of age (53.1% vs. 31.8%; P=0.01) and had distant metastasis at diagnosis (90.6% vs. 69.0%; P=0.006). The 5-year overall survival rate for patients diagnosed with bilateral disease was 70.5% (95% confidence interval, 45.1%-85.8%), compared with 62.4% (95% confidence interval, 59.7%-65%) for patients with unilateral disease (P=0.26). Compared with patients with unilateral disease, patients with bilateral adrenal neuroblastoma are younger, more likely to have distant metastasis, and have a favorable outcome.


The ovaries of Mecoptera: basic similarities and one exception to the rule.
Two entirely different types of ovaries (ovarioles) have been described in mecopterans. In the representatives of Meropeidae, Bittacidae, Panorpodidae and Panorpidae the ovarioles are of the polytrophic-meroistic type. Four regions: a terminal filament, germarium, vitellarium and ovariole stalk can be distinguished in the ovarioles. The germaria house numerous germ cell clusters. Each cluster arises as a result of 2 consecutive mitoses of a cystoblast and consists of 4 sibling cells. The oocyte always differentiates from one of the central cells of the cluster, whereas the remaining 3 cells develop into large, polyploid nurse cells. The vitellaria contain 7-12 growing egg chambers (= oocyte-nurse cell complexes). In contrast, the ovaries of the snow flea, Boreus hyemalis, are devoid of nurse cells and therefore panoistic (secondary panoistic). The ovarioles are composed of terminal filaments, vitellaria and ovariole stalks only; in adult females functional germaria are absent. Histochemical tests suggest that amplification of rDNA takes place in the oocyte nuclei. Resulting dense nucleolar masses undergo fragmentation into multiple polymorphic nucleoli. The classification of extant mecopterans as well as the phylogenetic relationships between Mecoptera and Siphonaptera are discussed in the context of presented data.


Novel therapeutic approaches for targeting tumor angiogenesis.
Current attempts to disrupt the complex process of tumor blood vessel formation are predominantly focused on targeting the vascular endothelial growth factor (VEGF)-VEGFR signaling pathway. Although clinically proven to inhibit VEGF and its receptors, these pharmacologic agents are selective, but not specific. Consequently, many of the approved inhibitors also impair other molecular targets leading to increased toxicity. Current efforts to unravel the complexity of tumor angiogenesis have identified several new candidates for antivascular therapy. In this review article, we identify well-established and novel angiogenic molecules and discuss benefits of the therapeutic approaches based on targeting of such factors.


Reduced cell-cell communication between mitotic and nonmitotic coupled cells.
The effects of mitosis on gap junctional intercellular communication (GJIC) were quantified in a clonal cell line of spontaneously immortalized rat granulosa cells (SIGC) using a fluorescence recovery after photobleaching assay. Reduction of GJIC was associated with the process of mitosis and was first apparent at the onset of prophase. Resumption of GJIC between newly divided cells and surrounding cells occurred slowly, requiring several hours following cytokinesis before reestablishment of maximal rates. Mitotic rates of GJIC in SIGC were comparable to values obtained in interphase cells partially uncoupled by 0.5 mM octanol. Limited studies of other cell lines generalized the mitotic-associated reduction of GJIC observed in SIGC. The data suggest that mitosis is one process which alters GJIC. This could be of significance when there is a change in the rate of proliferation, such as in the acquisition of immortalization, an early stage of transformation.


Autoimmune conditions and pancreatic cancer risk in older American adults.
Pancreatic cancer (PC) is highly fatal, and its incidence is increasing in the United States. Population-based registry studies suggest associations between a few autoimmune conditions and PC risk, albeit based on a relatively small number of cases. We conducted a population-based, nested case-control study to examine the associations between autoimmune conditions and PC risk within the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare population. Incident primary malignant PC cases (n = 80 074) were adults ≥66 years and diagnosed between 1992 and 2015. Controls (n = 320 296) were alive at the time cases were diagnosed and frequency-matched to cases (4:1 ratio) by age, sex, and year of diagnosis. We used multivariable-adjusted, unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 45 autoimmune conditions identified from Medicare claims. Eight autoimmune conditions including ankylosing spondylitis (OR = 1.45; 95% CI: 1.14-1.84), Graves' disease (OR = 1.18; 95% CI: 1.03-1.34), localized scleroderma (OR = 1.27; 95% CI: 1.06-1.52), pernicious anemia (OR = 1.08; 95% CI: 1.02-1.14), primary sclerosing cholangitis (OR = 1.37; 95% CI: 1.18-1.59), pure red cell aplasia (OR = 1.31; 95% CI: 1.16-1.47), type 1 diabetes (OR = 1.11; 95% CI: 1.07-1.15), and ulcerative colitis (OR = 1.18; 95% CI: 1.07-1.31) were associated with increased PC risk (false discovery rate-adjusted P values <.10). In subtype analyses, these conditions were associated with pancreatic ductal adenocarcinoma, whereas only ulcerative colitis was associated with pancreatic neuroendocrine tumors. Our results support the hypothesis that autoimmune conditions may play a role in PC development.


Measles Outbreak Investigation in Guradamole District of Bale Zone, South Eastern Ethiopia, 2021.
Measles is a highly contagious viral illness and globally, 142,300 people died from measles in 2018. On 25 March 2021, an outbreak of measles was reported from Guradamole district Bale Zone Southeast Ethiopia. Hence, we investigated to determine existence of the outbreak and to identify the associated factors. Descriptive and 1:2 unmatched case-control study was done in Guradamole district from March 25 to April 9/2021. For the descriptive study, a total of 98 cases were used. To identify the factor associated with the outbreak, 60 cases were selected by computer-generated simple random method by using line list as a sampling frame and 120 controls were studied. Active cases were identified through home-to-home searching in affected kebeles and controls were selected from neighbors of cases. Five serum samples were taken and an IgM test was done to confirm cases. Cases were any person who developed fever, maculopapular rash and cough, coryza or conjunctivitis while controls were without such diagnosis. We collected data by using a structured questionnaire, cases were described by time, place, and person; logistic regression was used to identify factors associated with measles. In the multivariable analysis P-value <0.05 was declared statistical significance. Overall, 98 cases were identified with an overall attack rate of 12/1000 population and a case fatality rate (CFR) of 7%. The highest attack rate (38/1000 population) and CFR (57%) were among children aged <59 months. Vaccination efficacy was calculated to be 82.6%. Being unvaccinated (adjusted odds ratio/AOR=5.66, 95% confidence interval, CI: 1.24-25.81), contact with patient (AOR=3.24, 95%CI: 1.03-10.17), moderate malnutrition (AOR=4.34, 95%CI: 2.14-8.814), distance from health facility (AOR=4.58, 95%CI: 1.39-15.19) and history of travel to affected area (AOR=3.99, 95%CI: 1.31-12.19) were shown significant associated with measles infection. The attack and fatality rate of the investigation were high. Being unvaccinated, distant from the health facility, malnutrition, and history of contact with measles case were associated with the outbreak. We recommend conducting vaccination campaigns, interventions to malnutrition, and strengthening routine immunization programs to reduce future measles outbreaks.


Effects of minor constituents (non-glyceride compounds) of virgin olive oil on plasma lipid concentrations in male Wistar rats.
We aimed to assess the effects of minor constituents (MC) from virgin olive oil upon the plasma lipid profile of experimental animals. Therefore, 32 Wistar rats were fed for 6 weeks with one of four different diets with a similar fatty acid composition but different MC: high-oleic sunflower oil (HOSO), virgin olive oil (VOO), 400%-MC enriched olive oil (EOO) and MC poor (impoverished) olive oil (IOO). At the end of the week 6 of dietary treatment, blood samples were obtained for analysis of lipid composition. A statistically significant influence was observed upon both total HDL (1.593+/-0.4, 1.204+/-0.212, 0.991+/-0.244 and 0.827+/-0.279 mmol/L for EOO, HOSO, VOO and IOO, respectively, Kruskal-Wallis test, P<0.05) and HDL(2)cholesterol levels (1.16+/-0.26, 0.576+/-0.191, 0.585+/-0.216 and 0.583+/-0.207 mmol/L for EOO, HOSO, VOO and IOO, respectively, Kruskal-Wallis test, P<0.05). No statistically significant effect was observed upon LDL-cholesterol or triglycerides. Thus, MC supplementation has beneficial effects on HDL concentrations in Wistar rats.


A New Pressure Guided Management Tool for Epidural Space Detection: Feasibility Assessment on a Simulator.
The detection of epidural space is usually performed by the technique of loss of resistance (LOR) without technological support, although there are few commercial options. We sought to design and develop a new noninvasive system able to detect the LOR without any changes to the conventional procedure. It allows detecting the LOR by a custom made algorithm. The system provides a visual and acoustic feedback when the LOR is detected. We optimized the detection algorithm and investigated the performance of the system during experiments on a custom simulator. During the experiments performed by 10 anesthetists and 10 trainees, the pressure exerted on the syringe plunger was monitored using the custom-made system. Each participant performed four experiments using the system on the simulator. The performance of the system in LOR detection was evaluated comparing the feedback activation and the breaches of the last layer of the simulator. Moreover, each participant filled out a questionnaire to assess how the procedure with the simulator mimics the clinical scenario. A higher questionnaire score corresponds to a more realistic condition (0 = not real, 5 = extremely real). Results showed that the LOR was detected in 74 of the 80 trials (92.5% of the cases); the anesthetists obtained better results than trainees: 97.5 versus 87.5%. The questionnaires showed that all the participants found the trial realistic (score ≥3); anesthetists found it more realistic than trainees (4.2 ± 0.78 vs. 3.8 ± 0.78, mean ± SD). In summary, the proposed system successfully detected the LOR in the large part of the trials. The participants found the trials realistic. A higher success rate was observed in the anesthetists group.


A physiologically based pharmacokinetic model of zidovudine (AZT) in the mouse: model development and scale-up to humans.
After having been used in treating HIV infection for a decade, zidovudine (AZT) continues to be an essential component of antiretroviral regimens. Because antiviral responses and toxicity of AZT seem to be related to cells in specific target tissues, being able to understand and predict the distribution of AZT into different pharmacologically and toxicologically relevant tissues is therefore critically important to improving the efficacy and minimizing the toxicity of AZT therapy. This study was designed to develop a physiologically based pharmacokinetic model to help describe and predict the time course of AZT levels in different tissues. The model was developed in the mouse and then scaled up to predict human situations.


Investigational C-C chemokine receptor 2 antagonists for the treatment of autoimmune diseases.
C-C chemokine receptor 2 (CCR2) antagonists belong to a group of chemokine blockers, which represent a new strategy for inflammatory diseases treatment by interfering with the complex system of chemokines and their receptors. A number of CCR2 antagonists are being developed for treatment of autoimmune diseases by different pharmaceutical and biotechnological companies. In this article the dark and the bright side of therapeutic CCR2 antagonism is discussed, with a view to its potential efficacy in various autoimmune diseases, in which clinical trials are already in progress, such as multiple sclerosis and rheumatoid arthritis. We describe different modes of possible interactions with CCR2-chemokine CC motif ligand 2 (CCL2) axis, usefulness of experimental animal models, continuing clinical trials and future perspectives of CCR2 antagonists. Until now only a few peer-reviewed articles providing data on the progress of preclinical and clinical trials with CCR2 antagonists have been published; therefore, we also present data based on preliminary reports, obtained from a number of press releases, conference communications and from the PharmaProjects database. Although there is growing evidence for a great therapeutic potential of CCR2 blockade in autoimmune diseases, especially well documented in experimental animal models, so far clinical trials with CCR2 antagonists in humans have been moderately encouraging or even disappointing, indicating a need to further elucidate the complex system of chemokine interactions.


Drug-induced fibrosis: interference with the intracellular collagen degradation pathway.
Drug-induced fibrosis and overgrowth of the extracellular matrix are high prevalence lesions of the oral mucosa. Drugs, such as dilantin, cyclosporin A and nifedipine can cause the gum tissues to overgrow, thereby preventing normal mastication and promoting infection. The causes of these disorders are poorly understood but recent evidence suggests that a common pathway targeted by these three drugs is the regulation of the intracellular pathway of collagen degradation. In this review, recent data that implicate calcium deregulation of the critical actin-dependent binding step of collagen phagocytosis will be discussed. These new insights highlight the need for a greater choice of medications for the treatment of transplant rejection and epilepsy to reduce the side effect of gingival overgrowth.


Optic neuritis associated with adalimumab in the treatment of uveitis.
Tumor necrosis factor (TNF) inhibitors such as adalimumab are increasingly used in the treatment of ocular inflammatory disease refractory to standard therapies. There is evidence that TNF inhibitors are associated with demyelinating neurologic events. The authors report a case of optic neuritis and multiple sclerosis developing in association with the use of adalimumab for the treatment of bilateral chronic granulomatous iridocyclitis and multifocal choroiditis. They also review the available literature on cases of optic neuritis occurring in the setting of TNF inhibition. The authors identified 21 cases of optic neuritis associated with TNF inhibition; 36% of cases with available MRI results had evidence of other demyelinating lesions in the CNS. The strong association between TNF inhibitors and CNS demyelination may represent an adverse effect of these drugs. Ophthalmologists should recognize the relationship between TNF inhibitors and demyelinating disease, as it can present initially with visual symptoms.


Tumor-associated APE1 variant exhibits reduced complementation efficiency but does not promote cancer cell phenotypes.
Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. Environ. Mol. Mutagen. 58:84-98, 2017. © 2017 Wiley Periodicals, Inc.


[Hemodilution in acute arterial circulatory disorders of the retina].
20 patients (age: 68 +/- 9 years) with an acute central artery obstruction of the retina were examined in a prospective study. All patients received a hyper- or isovolemic hemodilution depending on the haematocrit value for a period of 10 days. Clinical, hemodynamical and rheological data of these patients were recorded before therapy, after 10 days and after 6 weeks. Under this therapy, 10 patients presented an improved central vision by 2 or more stages. The degree of the distributed circulation can be determined by means of the arteriovenous passage time (AVP) and the dye bolus velocity (MDV). Compared to a control group, a significantly increased arterious-venous passage time and decreased dye bolus velocity can be observed initially. The values after 10 days of therapy and after 6 weeks were significantly improved (p less than 0.01) compared to the initial values.


M-DNA: A complex between divalent metal ions and DNA which behaves as a molecular wire.
M-DNA is a complex of DNA with divalent metal ions (Zn(2+), Co(2+), or Ni(2+)) which forms at pH conditions above 8. Upon addition of these metal ions to B-DNA at pH 8.5, the pH decreases such that one proton is released per base-pair per metal ion. Together with previous NMR data, this result demonstrated that the imino proton in each base-pair of the duplex was substituted by a metal ion and that M-DNA might possess unusual conductive properties. Duplexes of 20 base-pairs were constructed with fluorescein (donor) at one end and rhodamine (acceptor) at the other. Upon formation of M-DNA (with Zn(2+)) the fluorescence of the donor was 95 % quenched. Fluorescence lifetime measurements showed the presence of a very fast component in the decay kinetics with tau</=10 ps. The fast component was absent in B-DNA and in M-DNA lacking an acceptor chromophore; a result which is only consistent with electron transfer. Efficient signal transduction was also observed between the two fluorophores separated by 54 base-pairs (over 150 A) in an M-DNA duplex. The addition of a sequence-specific DNA-binding protein prevented the flow of electrons and this was reversed by protease digestion. Therefore, M-DNA behaves as a molecular wire and could be manipulated to prepare self-assembling electronic circuits.


Reversal of factor Xa inhibitors associated intracranial haemorrhage at a tertiary medical centre.
Prior to the approval of andexanet, there were no FDA-approved reversal agents indicated for the treatment of factor Xa inhibitor (FXaI) associated major bleed. Four-factor prothrombin complex concentrate (4F-PCC) has been widely used off-label for FXaI-associated bleeding. The purpose of this study was to compare the effectiveness and safety of andexanet and 4F-PCC for the reversal of FXaI-associated intracranial haemorrhage. The primary end point is in-hospital mortality; secondary endpoints include haemostatic efficacy and safety. This study is a singlecentre, retrospective chart review, including patients admitted between 1 January 2016 and 15 August 2019, who received 4F-PCC or andexanet for the management of FXaI-associated intracranial haemorrhage. Of the 45 patients included in this study, 23 patients were in the andexanet group and 22 were in the 4F-PCC group. At index admission, mean age was 76 years and the majority of patients (64%) were on apixaban with 33% presented with Glasgow Coma Scale 24 (GCS) score less than 12. At hospital discharge, 47% of patients in the andexanet group had died or discharged to hospice compared with 45% in the 4F-PCC group. No thromboembolic events were observed in either group within 5 days after administration of the reversal agent. The results of this study suggest that haemostasis and mortality at discharge during the index hospitalization appears to be similar between groups. Prospective randomized control trials comparing safety and efficacy of andexanet and 4F-PCC are needed.


Role of a genetic variant on the 15q25.1 lung cancer susceptibility locus in smoking-associated nasopharyngeal carcinoma.
The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC). In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16-2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23-3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57-7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011). Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts.


Indoor gardening older adults: effects on socialization, activities of daily living, and loneliness.
This study examined the effects of indoor gardening on socialization, activities of daily living (ADLs), and perceptions of loneliness in elderly nursing home residents. A total of 66 residents from two nursing homes participated in this two-phase study. In phase one, experimental group 1 participated once a week for 5 weeks in gardening activities while a control group received a 20-minute visit. While no significant differences were found between groups in socialization or perceptions of loneliness, there were significant pretest-posttest differences within groups on loneliness and guidance, reassurance of worth, social integration, and reliable alliance. The results also demonstrated gardening interventions had a significant effect on three ADLs (transfer, eating, and toileting). Phase two examined differences in the effects of a 5-week versus a 2-week intervention program. Although no significant within-group differences were noted in socialization, loneliness, or ADLs, the 5-week program was more effective in increasing socialization and physical functioning.


MODERN METHODS IN OTORHINOLARYNGOLOGY: POWERED-SHAVER ADENOIDECTOMY.
Endoscopic adenoidectomy with shaver is a safe, precise and fast procedure with minimal blood loss. With the help of this method, adenoids are completely removed without damage to adjacent tissues. Use of endoscope provides the possibility to display the operation on the screen in enlarged format and if applicable, the operation may be recorded. Controlled resection of tissues with shaver minimizes complications to the extent possible. 50 patients have been participated in the prospective study, all these patients had adenoidectomy with shaver, within the period from January 2019 to June 2020 inclusive. Age range was 2-26 years old. In order to determine efficacy of the method during the operation course, attention is to be paid to the following criteria: duration of the operation, blood loss, complications, perfection, depth of wound, satisfaction of a surgeon and recovery period. Average duration of the operation accounted for 15 minutes (10-20 minutes) and average blood loss was 30ml (within the range of 24-42ml). Complete resection was made under visual control amid insignificant complications, adequate depth of wound and surgeons' high satisfaction was achieved. Adenoidectomy with shaver is a fast, precise and safe procedure. The operation is made through full visual control, accordingly, complete resection of adenoids is carried out without damage to adjacent tissues ensuring a minimum chance for postoperative complications.


Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma.
The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas. Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors. NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC. NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.


[Ruptured arteriovenous malformation during pregnancy with special reference to diagnostic X-ray exposure. Case report].
A 32-year-old female (gravida 2, para 2) was admitted at 15 weeks of gestation with a chief complaint of left homonymous hemianopsia accompanied by frontal headache. Computed tomography scan and cerebral angiography were performed with the lead shield and probe for X-ray exposure placed on the patient's body. Angiography revealed an arteriovenous malformation (AVM) located in the posterior part of the right temporal lobe. Total dose of the diagnostic X-ray radiated to the fetus was measured 2.5 mrem at the most. The AVM and the hematoma were totally removed successfully at 19 weeks of gestation. A male infant weighing 3180 g was delivered at full term by cesarean section without congenital anomalies and he has been growing up without mental deficits. These results suggest that diagnostic X-ray examination during pregnancy has little risk and that surgical treatment should be given to the mother immediately after the rupture of an AVM if she is in good condition and the gestational date is past 12 weeks.


African vs. Caucasian and Asian difference for the association of interleukin-10 promotor polymorphisms with type 2 diabetes mellitus (a meta-analysis study).
Interleukin-10 (IL-10) is a multifunctional regulatory cytokine that might be associated with increased risk of type 2 diabetes mellitus (T2DM). IL-10 gene polymorphisms have been reported to be associated with T2DM in several ethnic populations with controversial results. This work is an updated meta-analysis aiming at the evaluation of the association between IL-10 gene polymorphisms: rs1800872 (- 592 C > A), rs1800896 (- 1082 A > G) and rs1800871 (- 819 C > T) with the risk of T2DM. All available full text studies published up to July 2015 were included in this meta-analysis. Mainly Pubmed and Science Direct databases were searched for all eligible studies pertinent to testing the association between IL-10 gene polymorphisms with the susceptibility to T2DM. Further analyses of the pooled and stratified data in terms of individual polymorphic types and subject ethnicity were done and assessed using varied genetic models. Fifteen case-control studies with a total of 26 comparisons (10 for IL-10 - 592 C > A rs1800872, 11 for IL-10 - 1082 A > G rs1800896 and 5 for IL-10 - 819 C > T rs1800871 polymorphisms) met our inclusion criteria. IL-10 - 1082 A > G polymorphism was the only one to show an association with T2DM in all pooled sample particularly among Asian and European (high frequency of the G allele) ethnic groups. On the other hand, IL-10 - 592 C > A and - 819 C > T were significantly associated with T2DM only among African subjects. This meta-analysis demonstrated that IL-10 - 1082 A > G polymorphism was associated with increased risk of development of T2DM in total subjects no matter was their ethnic background, while both IL-10 - 592 C > A and - 819 C > T polymorphisms were associated with that risk only among African subjects.


Activation of nucleotide-binding oligomerization domain 1 (NOD1) receptor signaling in Labeo rohita by iE-DAP and identification of ligand-binding key motifs in NOD1 by molecular modeling and docking.
The nucleotide-binding oligomerization domain 1 (NOD1) receptor recognizes various pattern-associated structures of microbes through its leucine-rich repeat (LRR) domain and activates signaling cascades to induce innate immunity. This report describes the activation of NOD1 receptor signaling by gamma-D-glutamyl-meso-diaminopimelic acid (or γ-D-Glu-mDAP [iE-DAP]) in a commercially important fish species, rohu (Labeo rohita). It also described critical motifs in the NOD1-LRR domain that could be involved in binding iE-DAP, lipopolysaccharide (LPS), and polyinosinic:polycytidylic acid (poly I:C). The activation of NOD1 receptor signaling was studied by injecting iE-DAP, and analysis of tissue samples for NOD1 and receptor-interacting serine/threonine kinase (RICK) expression was done by quantitative real-time polymerase chain reaction (qRT-PCR) assay. To identify ligand-binding motifs in NOD1, the 3D model of NOD1-LRR was generated, followed by a 6-ns molecular dynamics simulation. Molecular docking of LPS with NOD1-LRR was executed at the Hex and PatchDock servers, and iE-DAP and poly I:C in the AutoDock 4.2, FlexX 2.1, Glide 5.5, and GOLD 4.1 programs. The results of qRT-PCR revealed significant (p < 0.05) upregulation of NOD1 and RICK expression. Molecular docking revealed that the amino acid residues at LRR1-2, LRR3-7, and LRR8-9 could be involved in poly I:C, LPS, and iE-DAP binding, respectively. In fish, this is the first report describing the 3D structure of NOD1-LRR and its critical ligand-binding motifs.


Evaluation of new broth media for microdilution antibiotic susceptibility testing of Lactobacilli, Pediococci, Lactococci, and Bifidobacteria.
Nine pure or mixed broth media were evaluated for their suitabilities to determine MICs in a microdilution test of 19 antibacterial agents for lactic acid bacteria (LAB) of the genera Lactobacillus, Pediococcus, Lactococcus, and Bifidobacterium. A mixed formulation of Iso-Sensitest broth (90%) and deMan-Rogosa-Sharpe broth (10%) with or without supplementation with L-cysteine, referred to as the LAB susceptibility test medium, provided the most optimal medium basis in terms of growth support of nonenterococcal LAB and correct indication of MICs of international control strains.


Altered 3D chromatin structure permits inversional recombination at the IgH locus.
Immunoglobulin heavy chain (IgH) genes are assembled by two sequential DNA rearrangement events that are initiated by recombination activating gene products (RAG) 1 and 2. Diversity (DH) gene segments rearrange first, followed by variable (VH) gene rearrangements. Here, we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments. DH gene segments, which recombine by deletion of intervening DNA, must be located within a RAG1/2 scanning domain for efficient recombination. In the absence of intergenic control region 1, a regulatory sequence that delineates the RAG scanning domain on wild-type IgH alleles, VH and DH gene segments can recombine with each other by both deletion and inversion of intervening DNA. We propose that VH gene segments find their targets by distinct mechanisms from those that apply to DH gene segments. These distinctions may underlie differential allelic choice associated with each step of IgH gene assembly.