Human mammary artery endothelial sparing with fibrous jaw clamping.
Temporary clamping of the internal mammary artery pedicle is required for visualization during coronary artery bypass grafting. A nylon fibril jaw surface has been developed for these clamps that exerts pressure only at discrete sites on the pedicle surface. The effect of this new jaw surface on endothelial cell function and integrity after compression is investigated in this study. Internal mammary artery specimens from 10 patients each were divided into three separate rings, and two of these rings were clamped for 30 minutes with either a smooth or fibrous jaw clamp. Isometric tensions were measured in organ chambers after contraction by relaxing the rings with the endothelium-dependent agent acetylcholine followed by the endothelium-independent agent sodium nitroprusside. The intimal surfaces of similar rings were silver stained to assess the percentage of intact endothelium. Endothelium-dependent relaxation was spared after fibrous jaw clamping (75% versus 89%) but significantly impaired after smooth jaw clamping (25% versus 89%; p < 0.001). Endothelium-independent relaxation was unaffected by either intervention. The percentage of remaining intact endothelium upon silver staining was significantly less after smooth than after fibrous jaw clamping (24% versus 48%; p < 0.01). Foam silicone with nylon fibrils on the jaw surface of internal mammary artery clamps preserves endothelial cell function and integrity. The remaining undamaged cells also may facilitate the subsequent regeneration of a confluent endothelial cell layer.


Dynamic metabolic reprogramming of steroidal glycol-alkaloid and phenylpropanoid biosynthesis may impart early blight resistance in wild tomato (Solanum arcanum Peralta).
Exploration with high throughput leaf metabolomics along with functional genomics in wild tomato unreveal potential role of steroidal glyco-alkaloids and phenylpropanoids during early blight resistance. Alternaria solani severely affects tomato (Solanum lycopersicum L.) yield causing early blight (EB) disease in tropical environment. Wild relative, Solanum arcanum Peralta could be a potential source of EB resistance; however, its underlying molecular mechanism largely remains unexplored. Hence, non-targeted metabolomics was applied on resistant and susceptible S. arcanum accessions upon A. solani inoculation to unravel metabolic dynamics during different stages of disease progression. Total 2047 potential metabolite peaks (mass signals) were detected of which 681 and 684 metabolites revealed significant modulation and clear differentiation in resistant and susceptible accessions, respectively. Majority of the EB-triggered metabolic changes were active from steroidal glycol-alkaloid (SGA), lignin and flavonoid biosynthetic pathways. Further, biochemical and gene expression analyses of key enzymes from these pathways positively correlated with phenotypic variation in the S. arcanum accessions indicating their potential role in EB. Additionally, transcription factors regulating lignin biosynthesis were also up-regulated in resistant plants and electrophoretic mobility shift assay revealed sequence-specific binding of rSaWRKY1 with MYB20 promoter. Moreover, transcript accumulation of key genes from phenylpropanoid and SGA pathways along with WRKY and MYB in WRKY1 transgenic tomato lines supported above findings. Overall, this study highlights vital roles of SGAs as phytoalexins and phenylpropanoids along with lignin accumulation unrevealing possible mechanistic basis of EB resistance in wild tomato.


Clinical implications of epigenetic alterations in human thoracic malignancies: epigenetic alterations in lung cancer.
Besides known genetic aberrations, epigenetic alterations have emerged as common hallmarks of many cancer types, including lung cancer. Epigenetics is a process involved in gene regulation, mediated via DNA methylation, histone modification, chromatin remodeling, and functional noncoding RNAs, which influences the accessibility of the underlying DNA to transcriptional regulatory factors that activate or repress expression. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Since epigenetic therapy is now in clinical use in hematopoietic diseases and undergoing trials for lung cancer, a better understanding of epigenetic abnormalities is desired. Recent technologies for high-throughput genome-wide analyses for epigenetic modifications are promising and potent tools for understanding the global dysregulation of cancer epigenetics. In this chapter, studies of epigenetic abnormality and its clinical implication in lung cancers are discussed.


Heteromerous interactions among glycolytic enzymes and of glycolytic enzymes with F-actin: effects of poly(ethylene glycol).
Interactions of glucose-6-phosphate isomerase (D-glucose-6-phosphate ketol-isomerase, EC 184.108.40.206), aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate lyase, EC 220.127.116.11), glyceraldehyde-3-phosphate dehydrogenase (D-glyceraldehyde-3-phosphate:NAD+ oxidoreductase (phosphorylating), EC 188.8.131.52), triose-phosphate isomerase (D-glyceraldehyde-3-phosphate ketol-isomerase, EC 184.108.40.206), phosphoglycerate mutase (D-phosphoglycerate 2,3-phosphomutase, EC 126.96.36.199), phosphoglycerate kinase (ATP:3-phospho-D-glycerate 1-phosphotransferase, EC 2.7.3), enolase (2-phospho-D-glycerate hydro-lyase, EC 184.108.40.206), pyruvate kinase (ATP:Pyruvate O2-phosphotransferase, EC 18.104.22.168) and lactate dehydrogenase [S)-lactate:NAD+ oxidoreductase, EC 188.8.131.52) with F-actin, among the glycolytic enzymes listed above, and with phosphofructokinase (ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 184.108.40.206) were studied in the presence of poly(ethylene glycol). Both purified rabbit muscle enzymes and rabbit muscle myogen, a high-speed supernatant fraction containing the glycolytic enzymes, were used to study enzyme-F-actin interactions. Following ultracentrifugation, F-actin and poly(ethylene glycol) tended to increase and KCl to decrease the pelleting of enzymes. In general, the greater part of the pelleting occurred in the presence of both F-actin and poly(ethylene glycol) and the absence of KCl. Enzymes that pelleted more in myogen preparations than as individual purified enzymes in the presence of poly(ethylene glycol) and the absence of F-actin were tested for specific enzyme-enzyme associations, several of which were observed. Such interactions support the view that the internal cell structure is composed of proteins that interact with one another to form the microtrabecular lattice.


Management of the cervico-petrous internal carotid artery in class C tympanojugular paragangliomas.
Management of the cervical and petrous internal carotid artery (ICA) is frequently required in Fisch class C tympanojugular paragangliomas (TJPs). The purpose of this study was to discuss the perioperative intervention of the ICA in patients who underwent surgical resection of a TJP. A retrospective study of 237 patients surgically treated for Fisch class C TJPs was done to identify cases that required ICA management. Management of the ICA was required in 176 patients (74.2%). Forty-two patients required just an ICA decompression, 88 underwent a subperiosteal dissection, 19 underwent subadventitial dissection without intraluminal stenting, 17 underwent subadventitial dissection with intraluminal stenting, and 12 underwent arterial resection after permanent balloon occlusion. There were no complications associated with the endovascular procedures. Gross total tumor resection was achieved in 91.5% of the cases. Preoperative endovascular intervention, in selected cases, facilitates gross total tumor removal and significantly reduces the risk of an intraoperative ICA injury. © 2015 Wiley Periodicals, Inc. Head Neck 38: 899-905, 2016.


Fasting promotes acute hypoxic adaptation by suppressing mTOR-mediated pathways.
Rapid adaptation to a hypoxic environment is an unanswered question that we are committed to exploring. At present, there is no suitable strategy to achieve rapid hypoxic adaptation. Here, we demonstrate that fasting preconditioning for 72 h reduces tissue injuries and maintains cardiac function, consequently significantly improving the survival rates of rats under extreme hypoxia, and this strategy can be used for rapid hypoxic adaptation. Mechanistically, fasting reduces blood glucose and further suppresses tissue mTOR activity. On the one hand, fasting-induced mTOR inhibition reduces unnecessary ATP consumption and increases ATP reserves under acute hypoxia as a result of decreased protein synthesis and lipogenesis; on the other hand, fasting-induced mTOR inhibition improves mitochondrial oxygen utilization efficiency to ensure ATP production under acute hypoxia, which is due to the significant decrease in ROS generation induced by enhanced mitophagy. Our findings highlight the important role of mTOR in acute hypoxic adaptation, and targeted regulation of mTOR could be a new strategy to improve acute hypoxic tolerance in the body.


Periodontal attachment loss in patients after head and neck radiation therapy.
The purpose of this study was to determine the potential impact of head and neck radiation therapy on the progression of periodontal attachment loss. Ten patients who received unilateral radiation fields that included the dentition were assessed before radiation treatment and after irradiation at a mean age of 6.01 years. Complete oral, dental, and periodontal examinations were completed by one examiner. The results were assessed through use of paired t tests. More teeth were extracted because of periodontal disease in the field of radiation after irradiation. Remaining teeth in the radiated volume showed an increase in probing depth of 0.82 mm in comparison with 0.40 mm for teeth in the nonradiated region (P = .05). Recession on the facial aspects was 1.88 mm for teeth in the radiated volume and 1.16 mm for teeth in the nonradiated region (P = .001), and recession on the lingual aspects was 2.10 for teeth in the radiated volume and 0.91 for teeth in the nonradiated region (P = .05). Mean total attachment loss was 2.81 mm for teeth in the radiated sites; this compared with 1.43 mm for teeth in the nonradiated sites (P = .003). Increased mobility of teeth in the high-dose fields was seen (P = .02). This study showed that tooth loss and greater periodontal attachment loss occur in teeth that are included within high-dose radiated sites of patients treated with irradiation therapy for cancer. These findings should be considered in preradiation treatment planning.


Expression profiling of microRNAs and isomiRs in conventional central chondrosarcoma.
Conventional central chondrosarcoma (CCC) is a malignant bone tumor that is characterized by the production of chondroid tissue. Since radiation therapy and chemotherapy have limited effects on CCC, treatment of most patients depends on surgical resection. This study aimed to identify the expression profiles of microRNAs (miRNAs) and isomiRs in CCC tissues to highlight their possible participation to the regulation of pathways critical for the formation and growth of this type of tumor. Our study analyzed miRNAs and isomiRs from Grade I (GI), Grade II (GII), and Grade III (GIII) histologically validated CCC tissue samples. While the different histological grades shared a similar expression profile for the top abundant miRNAs, we found several microRNAs and isomiRs showing a strong different modulation in GII + GIII vs GI grade samples and their involvement in tumor biology could be consistently hypothesized. We then in silico validated these differently expressed miRNAs in a larger chondrosarcoma public dataset and confirmed the expression trend for 17 out of 34 miRNAs. Our results clearly suggests that the contribution of miRNA deregulation, and their targeted pathways, to the progression of CCC could be relevant and strongly indicates that when studying miRNA deregulation in tumors, not only the canonical miRNAs, but the whole set of corresponding isomiRs should be taken in account. Improving understanding of the precise roles of miRNAs and isomiRs over the course of central chondrosarcoma progression could help identifying possible targets for precision medicine therapeutic intervention.


Validation and uncertainty assessment of rapid extraction and clean-up methods for the determination of 16 organochlorine pesticide residues in vegetables.
Rapid and practical extraction methods were developed using dichloromethane and ethyl acetate for the routine determination of 16 organochlorine pesticide residues and applied to approximately 30 fresh vegetables (tomato, cucumber and pepper) by using GC-ECD. The procedures were validated. Measurement uncertainties were calculated by applying bottom-up approach. The average recoveries obtained for each pesticide ranged between 65 and 102% at three fortification levels. The uncertainties of the analytical methods were lower than 21 and 16% with and without recovery correction, respectively. The calculated limits of detection and quantification were typically less than 1 ng g(-1) that were much lower than the maximum residue levels.


A microcontinuum model for mechanical properties of esophageal tissue: experimental methodology and constitutive analysis.
Accurate material properties of tissues are a key factor for the improvement of medical procedures and treatments. Experimental data are essential in order to formulate and validate a useful constitutive model for predicting the mechanical behavior of tissues in these procedures. This study develops a comprehensive experimental protocol at multiple length scale levels in order to obtain stress-strain curves for esophagus tissue. This paper compares two different models: a conventional, non-linear elastic model, and a microcontinuum model based on fiber rearrangement. Also, a detailed description of the experimental procedure is provided. While the focus was on esophageal tissues, the experimental procedure and microcontinuum are considered widely applicable to other samples of soft tissue.


Synthesis, and spectroscopic and structural characterization of three new styrylquinoline-benzimidazole hybrids.
Three new 4-styrylquinoline-benzimidazole hybrids have been synthesized using a reaction sequence in which 2-methylquinoline precursors first undergo selective oxidation by selenium dioxide to form the corresponding 2-formylquinoline intermediates, followed by oxidative cyclocondensation reactions with benzene-1,2-diamine to yield the hybrid products. The formyl intermediates and the hybrid products have all been fully characterized using a combination of IR, 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry, and the structures of the three hybrid products have been determined using single-crystal X-ray diffraction. Ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-chlorostyryl)quinoline-3-carboxylate, C27H20ClN3O2, (IIIa), and ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(2-methoxystyryl)quinoline-3-carboxylate, C28H23N3O3, (IIIb), both crystallize in the solvent-free form with Z' = 1, but ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-methylstyryl)quinoline-3-carboxylate, C28H23N3O2, (IIIc), crystallizes as a partial hexane solvate with Z' = 3, and the ester group in one of the independent molecules is disordered over two sets of atomic sites having occupancies of 0.765 (7) and 0.235 (7). The molecules of (IIIc) enclose continuous channels which are occupied by disordered solvent molecules having partial occupancy. In all of the molecules of (IIIa)-(IIIc), the styrylquinoline fragment is markedly nonplanar. Different combinations of N-H...O and C-H...π hydrogen bonds generate supramolecular assemblies which are two-dimensional in (IIIb) and (IIIc), but three-dimensional in (IIIa). Comparisons are made with the structures of some related compounds.


Inhibitory mechanism of oxethazaine on release of endogenous secretin and pancreatic response in dogs.
The mechanism by which oxethazaine inhibits hydrochloric acid stimulation of pancreatic secretion and the endogenous release of secretin was studied in six dogs prepared with pancreatic and gastric fistulae. Oxethazaine reduced both pancreatic secretion and plasma secretin concentration evoked by duodenal acidification, and the degree of inhibition was proportional to its dose. This drug did not inhibit the pancreatic secretion stimulated by the exogenous secretin. From kinetic analyses, it seems that oxethazaine acted as noncompetitive inhibitor of hydrogen ion on the chemoreceptors of the secretin-releasing cells in the duodenal mucosa. This may result in a decrease of secretin release from these cells and consequently of pancreatic secretion.


Purification and quantification of nivalenol.
A mean of 2.7 g fusarenon-X (FUS-X)/L was produced in cultures ofFusarium sp Fn-2B on SSA, a synthetic medium containing sucrose and asparagine. When culturing Fn-2B on several other media, or using otherFusarium strains, much lower concentrations of FUS-X or nivalenol (NIV) were obtained. The SSA-incubations with Fn-2B in an optimal volume of 100 mL were stopped just before reaching maximal FUS-X concentration and the start of conversion to NIV. FUS-X was extracted from the 22 days old cultures and partially purified on a silica gel column. It was then hydrolysed to NIV, which was rechromatographed on silica and crystallized.The purity and the chemical and physical properties of the NIV produced were investigated. Potential sources of error when quantifying NIV were also studied.


Is It All COVID-19? Resident Distress and Reasons for It in 2020.
For resident wellness, it is important to understand and discern the relative contributions of each factor to resident stress. After institutional review board approval, a 20-question survey instrument was provided to 90 residents across four specialties (Internal Medicine, Emergency Medicine, General Surgery, and Orthopedic Surgery) at a university-affiliated health system. The survey was completed from October through November 2020 by 63 residents for a 70% participation rate. Qualitative and quantitative analyses were used. The results showed a mean change in status in either direction of 2.66 points on an 11-point scale. Status changes were both positive (less stress) and negative (more stress). Related to the source of change in stress levels, 8 items were seen as predominantly influenced by residency training and 11 factors were predominantly influenced by the pandemic. One item was equally influenced by both. No item was primarily influenced by the sociopolitical climate. For 16 of the 20 items, changes in a negative direction were statistically greater than in a positive direction. Both positive and negative changes in resident stress status occurred during the pandemic period. Traditional residency stressors remained and because all of the factors were affected by both the pandemic and residency training, efforts to mitigate the negative effects of both need to continue.


Developing a Youth Contraception Navigator Program: A Human-Centered Design Approach.
To determine key elements of a contraception navigator program that provides a personalized approach to overcoming patient-specific barriers by a trained navigator in central Indiana. A human-centered design approach was used to engage adolescents and community stakeholders in co-design sessions. Sessions incorporated techniques, such as divergent brainwriting and journey maps, which led to the exploration of various themes that were ultimately used to inform key elements of the contraception navigator program. Adolescents aged 15-17 years (N = 35) and community stakeholders (N = 11) participated in co-design sessions. Analysis verified that the process of obtaining contraception for pregnancy prevention could be intimidating for young people. The importance of language, the presence of stigma, and the knowledge of side effects were all discussed. Essential elements of a contraceptive navigator program included building trust to ultimately co-create a plan that can overcome patient-specific barriers. Having a variety of communication methods available, as well as contraceptive side-effect support, will be essential. Using human-centered design techniques to engage adolescent and community stakeholders can help inform the development of a contraceptive navigator program. A trusted navigator that can address patient-specific barriers to contraception access both before and after contraception is obtained is a key element identified by stakeholders.


Preoperative vocal cord paralysis and its association with malignant thyroid disease and other pathological features.
Vocal cord paralysis (VCP) is found in both benign and malignant thyroid disease. This study was performed to determine if the presence of preoperative VCP predicts malignancy. A retrospective analysis was performed on a cohort of 1923 consecutive patients undergoing thyroid surgery. The incidence of preoperative VCP was recorded. Patient and nodule characteristics were correlated with final pathology. 1.3% of our cohort was found to have preoperative VCP. Malignant pathology was discovered in 76% of patients with preoperative VCP. Among these patients, 72% had a left sided paralysis. 10.5% of patients with preoperative VCP had perineural invasion (PNI) on final pathology, compared to 1.1% of patients with normal VC function. Preoperative VCP appears to be a strong, though not an absolute, indicator of malignancy. Most VCP were on the left side. Assessing for preoperative VCP is crucial in all patients who need thyroid surgery, as even benign nodules can be accompanied by preoperative vocal cord paralysis.


Radiological techniques in the examination of patients with headaches.
It can be said that in the majority of headache patients who have a long typical history, a negative neurologic examination, and a noncontributory general physical examination, radiologic studies will probably not give further pertinent information. Nevertheless, in a sufficient number of these patients, the noninvasive and essentially atraumatic procedures of plain skull radiography, computed tomography, and (as indicated) echoencephalography and radionuclide brain scanning will provide a considerable amount of information pertinent to the clinical problem. Hospitalization for angiography and, on occasion, pneumoencephalography or other special procedures, will then become indicated for those patients in whom an abnormality is found in these screening procedures.


Nucleotide sequence of Dictyostelium small nuclear RNA Dd8 not homologous to any other sequenced small nuclear RNA.
The cellular slime mold Dictyostelium discoideum, a lower eukaryote, was shown to contain several species of small nuclear RNA (Takeishi, K., and Kaneda, S. (1981) J. Biochem. (Tokyo) 90, 299-308; Wise, J. A., and Weiner, A. M. (1981) J. Biol. Chem. 256, 956-963). One of these RNAs, Dd9 or D2, was sequenced and found to be homologous to mammalian nucleolar U3 RNA. In the present study, the nucleotide sequence of another Dictyostelium small nuclear RNA Dd8 was determined by direct analysis. The sequence is: (formula; see text) Dd8 RNA contains high proportions of A (34%) and U (30%). No modified nucleotide could be detected in the internal region. Computer-assisted analysis of sequence homology indicated that Dd8 RNA is not homologous to any other small nuclear RNA species sequenced so far.


Social Media Listening and Digital Profiling Study of People With Headache and Migraine: Retrospective Infodemiology Study.
There is an unmet need for a better understanding and management of headache, particularly migraine, beyond specialist centers, which may be facilitated using digital technology. The objective of this study was to identify where, when, and how people with headache and migraine describe their symptoms and the nonpharmaceutical and medicinal treatments used as indicated on social media. Social media sources, including Twitter, web-based forums, blogs, YouTube, and review sites, were searched using a predefined search string related to headache and migraine. The real-time data from social media posts were collected retrospectively for a 1-year period from January 1, 2018, to December 31, 2018 (Japan), or a 2-year period from January 1, 2017, to December 31, 2018 (Germany and France). The data were analyzed after collection, using content analysis and audience profiling. A total of 3,509,828 social media posts related to headache and migraine were obtained from Japan in 1 year and 146,257 and 306,787 posts from Germany and France, respectively, in 2 years. Among social media sites, Twitter was the most used platform across these countries. Japanese sufferers used specific terminology, such as "tension headaches" or "cluster headaches" (36%), whereas French sufferers even mentioned specific migraine types, such as ocular (7%) and aura (2%). The most detailed posts on headache or migraine were from Germany. The French sufferers explicitly mentioned "headache or migraine attacks" in the "evening (41%) or morning (38%)," whereas Japanese mentioned "morning (48%) or night (27%)" and German sufferers mentioned "evening (22%) or night (41%)." The use of "generic terms" such as medicine, tablet, and pill were prevalent. The most discussed drugs were ibuprofen and naproxen combination (43%) in Japan; ibuprofen (29%) in Germany; and acetylsalicylic acid, paracetamol, and caffeine combination (75%) in France. The top 3 nonpharmaceutical treatments are hydration, caffeinated beverages, and relaxation methods. Of the sufferers, 44% were between 18 and 24 years of age. In this digital era, social media listening studies present an opportunity to provide unguided, self-reported, sufferers' perceptions in the real world. The generation of social media evidence requires appropriate methodology to translate data into scientific information and relevant medical insights. This social media listening study showed country-specific differences in headache and migraine symptoms experienced and in the times of the day and treatments used. Furthermore, this study highlighted the prevalence of social media usage by younger sufferers compared to that by older sufferers.


Three-Year Changes in Low-Income Children's Physical Activity: Prospective Influence of Neighborhood Environment and Parent Supportive Behavior.
To prospectively evaluate parent supportive behaviors (PSB) for child physical activity (PA) and neighborhood environment variables on changes in child PA over 3 years. Secondary data analysis of the Now Everybody Together for Amazing and Healthful Kids-Works study with 534 parent-child (age 2-4 years) dyads randomized to a community-based pediatric obesity prevention intervention for 3 years (92% retention). PSB and neighborhood environmental variables were examined in relation to changes in child moderate-to-vigorous PA (MVPA), light and sedentary activity, and screen time. Child and parent accelerometry data were collected at visit 0, 12, 24, and 36 months. Mixed multivariate models were used to examine independent and interactive effects of parent-level and neighborhood-level variables on changes in child PA outcomes. PSB significantly interacted with visit on change in child MVPA (β = 0.12) and sedentary behaviors (β = -0.18). Over 3 years, a 1-unit increase in PSB was associated with an average increase of 4.3 minutes/day of MVPA and an average decrease of 6.5 minutes/day of sedentary time. Significant main effects were observed for PSB and 3-year change in child screen time (β = -0.05). The children of parents with higher PSB at baseline watched an average of 1.8 fewer minutes/day of screen time compared with parents with lower baseline PSB. Neighborhood-level variables were not significantly associated with changes in child PA outcomes. Parents who increase their supportive behaviors for their child's PA have children who are more physically active and less sedentary over time. Interventions to increase preschool-age children's PA may enhance their effectiveness by targeting parents' supportive behaviors for their child's PA.


Prediction of mortality in pediatric burn injuries: R-baux score to be applied in children (pediatrics-baux score).
R-Baux score has obtained an acceptable validity and accuracy in predicting burn-related mortality. However, its usage and efficacy among pediatric burn patients has not been well documented. The aim of this study was to employ Pediatrics-Baux (P-Buax) score as modified version of R-Baux score in these patients to determine how it could be applicable in this population. Through a prospective study, 870 pediatric burn patients were enrolled. P-Baux and R-Baux scores were calculated for each patient and they were categorized to different groups according to these scores. Mortality and further death probability were measured for each subject and then analyzed by logistic regression model to reveal how they change in relation with age in pediatric burn patients. R-Baux score for 95% probability of death revealed a mean of 73 among patients of this study. Also P-Baux score was measured in these patients with inhalation injury which showed to be 55 for 95% probability of death. Results showed that age had a positive prognostic value in contrast to the negative prognostic value of Total Body Surface Area (TBSA) and inhalation injury. Our analysis showed that in children under the age of 15 years, age has a positive prognostic value while TBSA and inhalation injuries had negative prognostic values in relation to mortality. Hence, in contrast to the adult population, burn injury related mortality may be predicted by modified R-Baux score as (TBSA - age + [18×R]) which could be named as P-Baux score.


Crystal structure of an Anti-meningococcal subtype P1.4 PorA antibody provides basis for peptide-vaccine design.
In various western countries, subtype P1.4 of Neisseria meningitidis serogroup B causes the greatest incidence of meningococcal disease. To investigate the molecular recognition of this subtype, we crystallised a peptide (P1HVVVNNKVATH(P11)), corresponding to the subtype P1.4 epitope sequence of outer membrane protein PorA, in complex with a Fab fragment of the bactericidal antibody MN20B9.34 directed against this epitope. Structure determination at 1.95 A resolution revealed a unique complex of one P1.4 antigen peptide bound to two identical Fab fragments. One Fab recognises the putative epitope residues in a 2:2 type I beta-turn at residues P5NNKV(P8), whereas the other Fab binds the C-terminal residues of the peptide that we consider a crystallisation artefact. Interestingly, recognition of the P1.4 epitope peptide is mediated almost exclusively through the complementarity-determining regions of the heavy chain. We exploited the observed turn conformation for designing conformationally restricted cyclic peptides for use as a peptide vaccine. The conformational stability of the two peptide designs was assessed by molecular dynamics simulations. Unlike the linear peptide, both cyclic peptides, conjugated to tetanus toxoid as a carrier protein, elicited antibody responses in mice that recognised meningococci of subtype P1.7-2,4. Serum bactericidal assays showed that some, but not all, of the sera induced with the cyclic peptide conjugates could activate the complement system with titres that were very high compared to the titres induced by complete PorA protein in its native conformation administered in outer membrane vesicles.


Efficacy of argon-helium cryoablation and its effects on immune function of patients with neck malignant tumours.
Our study aimed to investigate the clinical efficacy of argon-helium cryoablation and its effects on the immune function of patients with neck malignant tumours. Retrospective study. Single-institution academic tertiary care centre. Totally, 180 patients harbouring head and neck malignant tumours were divided into the argon-helium cryoablation group (n = 150) and the radiotherapy group (n = 50). The efficacy of the two groups was compared, and the immune function was observed. The short-term clinical effect of the argon-helium cryoablation group was significantly higher than that of the radiotherapy group (P < .05). After treatment, the CD3+, CD4+, CD8+ and CD4+/CD8+ of the argon-helium cryoablation group were significantly better than those of the radiotherapy group (P < .001). The results of TNF-α, IL-1 β and CRP in the argon-helium cryoablation group were significantly better than that in the radiotherapy group (P < .001). Argon-helium cryoablation could effectively improve the immune function, 5-year survival rate and local remission rate.


Differential Gait Decline in Parkinson's Disease Enhances Discrimination of Gait Freezers from Non-Freezers.
Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD) for which treatments are limited. To develop neuroprotective strategies, determining whether disease progression is different in phenotypic variants of PD is essential. To determine if freezers have a faster decline in spatiotemporal gait parameters. Subjects were enrolled in a longitudinal study and assessed every 3- 6 months. Continuous gait in the levodopa ON-state was collected using a gait mat (Protokinetics). The slope of change/year in spatiotemporal gait parameters was calculated. 26 freezers, 31 non-freezers, and 25 controls completed an average of 6 visits over 28 months. Freezers had a faster decline in mean stride-length, stride-velocity, swing-%, single-support-%, and variability in single-support-% compared to non-freezers (p < 0.05). Gait decline was not correlated with initial levodopa dose, duration of levodopa therapy, change in levodopa dose or change in Montreal Cognitive Assessment scores (p > 0.25). Gait progression parameters were required to obtain 95% accuracy in categorizing freezers and non-freezers groups in a forward step-wise binary regression model. Change in mean stride-length, mean stride-width, and swing-% variability along with initial foot-length variability, mean swing-% and apathy scores were significant variables in the model. Freezers had a faster temporal decline in objectively quantified gait, and inclusion of longitudinal gait changes in a binary regression model greatly increased categorization accuracy. Levodopa dosing, cognitive decline and disease severity were not significant in our model. Early detection of this differential decline may help define freezing prone groups for testing putative treatments.


Enhancement of methane production from waste activated sludge using hybrid microbial electrolysis cells-anaerobic digestion (MEC-AD) process - A review.
Hybrid microbial electrolysis cells-anaerobic digestion (MEC-AD) was proved to increase methane productivity and methane yield of waste activated sludge (WAS) by establishing direct interspecies electron transfer method and enriching functional microorganisms. This review first summarized the pretreatment methods of WAS for MEC-AD and then reviewed the reactor configurations, operation parameters, and the economic benefit of MEC-AD. Furthermore, the enhancement mechanisms of MEC-AD were reviewed based on the analysis of thermodynamics and microbial community. It was found that the decrease of hydrogen partial pressure due to the hydrogenotrophic methanogens enriched in cathodic biofilm and direct interspecies electron transfer between exoelectrogens and anode were the core mechanisms for improving acidogenesis, acetogenesis, and methanogenesis. Finally, the potentially technological issues that need to be addressed to increase energy efficiency in large-scale MEC-AD processes were discussed.


Strain-Induced Quantum Spin Hall Effect in Two-Dimensional Methyl-Functionalized Silicene SiCH₃.
Quantum Spin Hall (QSH) has potential applications in low energy consuming spintronic devices and has become a researching hotspot recently. It benefits from insulators feature edge states, topologically protected from backscattering by time-reversal symmetry. The properties of methyl functionalized silicene (SiCH₃) have been investigated using first-principles calculations, which show QSH effect under reasonable strain. The origin of the topological characteristic of SiCH₃, is mainly associated with the s-pxy orbitals band inversion at Γ point, whilst the band gap appears under the effect of spin-orbital coupling (SOC). The QSH phase of SiCH₃ is confirmed by the topological invariant Z₂ = 1, as well as helical edge states. The SiCH₃ supported by hexagonal boron nitride (BN) film makes it possible to observe its non-trivial topological phase experimentally, due to the weak interlayer interaction. The results of this work provide a new potential candidate for two-dimensional honeycomb lattice spintronic devices in spintronics.


CAMOIP: a web server for comprehensive analysis on multi-omics of immunotherapy in pan-cancer.
Immune checkpoint inhibitors (ICIs) have completely changed the approach pertaining to tumor diagnostics and treatment. Similarly, immunotherapy has also provided much needed data about mutation, expression and prognosis, affording an unprecedented opportunity for discovering candidate drug targets and screening for immunotherapy-relevant biomarkers. Although existing web tools enable biologists to analyze the expression, mutation and prognostic data of tumors, they are currently unable to facilitate data mining and mechanism analyses specifically related to immunotherapy. Thus, we effectively developed our own web-based tool, called Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer (CAMOIP), in which we are able to successfully screen various prognostic markers and analyze the mechanisms involved in biomarker expression and function, as well as immunotherapy. The analyses include information relevant to survival analysis, expression analysis, mutational landscape analysis, immune infiltration analysis, immunogenicity analysis and pathway enrichment analysis. This comprehensive analysis of biomarkers for immunotherapy can be carried out by a click of CAMOIP, and the software should greatly encourage the further development of immunotherapy. CAMOIP provides invaluable evidence that bridges the information between the data of cancer genomics based on immunotherapy, providing comprehensive information to users and assisting in making the value of current ICI-treated data available to all users. CAMOIP is available at https://www.camoip.net.


High prevalence of small dense LDL as an underestimated component of heart transplantation-induced dyslipidemia: potential role in graft coronary vasculopathy?
Heart transplantation-induced dyslipidemia is a recognized risk factor for cardiac allograft vasculopathy that affects survival prognosis. Beyond increased lipids, low-density lipoprotein (LDL) size and systemic factors, including glucose intolerance, oxidative stress, and inflammation, must be taken into account as components of the atherosclerotic risk. The aim of this study was to explore the atherogenic profile of heart transplant recipients (HTR) by assessing lipid parameters, glycemia, oxidative stress status, and inflammation in 59 transplant patients (follow-up of 6 +/- 3 years) compared to 20 healthy volunteers. Classical hypercholesterolemia and hypertriglyceridemia were observed in HTR compared to controls, associated with increased apoCIII levels (0.13 +/- 0.6 vs 0.07 +/- 0.03 g/L, P < .01). Mean LDL size was reduced in HTR compared to controls (25.22 +/- 0.72 vs 26.06 +/- 0.54 nm, P < .001) with an abnormally high prevalence (69% vs 0%, P < .001) of small dense LDL (<25.5 nm). Hyperglycemia (7.3 +/- 3 vs 5.4 +/- 0.8 mmol/L, P < .05) and inflammation (high-sensitive CRP: 3.1 +/- 3 vs 1.6 +/- 0.9 mg/L, P < .001) were evidenced in HTR since no difference in oxidative stress parameters was observed. In conclusion, a high prevalence of small dense LDL is an important component of posttransplantation dyslipidemia.


Toxicity assessment on trophoblast cells for some environment polluting chemicals and 17β-estradiol.
The identification of reproductive toxicants is a major scientific challenge for human health. We investigated the effects of a selected group of environmental polluting chemicals mostly provided with estrogenic activity on the human trophoblast cell lines BeWo and HTR-8/SVneo. Cells were exposed for 24h to various concentrations (from 0.1 pM to 1 mM) of atrazine (ATR), diethylstilbestrol (DES), para-nonylphenol (p-NP), resveratrol (RES) and 17 β-estradiol (E2) and assayed for cell viability and human beta-Chorionic Gonadotropin (β-hCG) secretion. Decrease of cell viability as respect to control, vehicle-treated, cultures was obtained for all chemicals in the concentration range of 1 μM-1 mM in both cell types. A parallel decrease of β-hCG secretion was observed in BeWo cells, at 1 μM-1 mM concentrations, with the only exception of ATR which caused an increase at concentrations up to 1mM. β-hCG release was also unexpectedly inhibited by ATR, DES, p-NP and RES at non-toxic (pM-nM) concentrations. These findings raise concern about the negative, potential effects of various environmental polluting chemicals on pregnancy success and fetal health.


Anchorage of Au3+ into Modified Isoreticular Metal-Organic Framework-3 as a Heterogeneous Catalyst for the Synthesis of Propargylamines.
Postsynthetic modification of metal-organic framework is a general and practical approach to access MOF-based catalysts bearing multiple active sites. The isoreticular metal-organic framework-3 (IRMOF-3) was modified with lactic acid through condensation reaction of the carboxyl group of lactic acid and amino group present in IRMOF-3 frameworks. Au3+ was subsequently anchored onto the metal-organic framework IRMOF-3 using postsynthetic modification. The synthezized IRMOF-3-LA-Au (LA = lactic acid) was characterized by powder X-ray diffraction, N2 adsorption-desorption, infrared spectroscopy, liquid-state nuclear magnetic resonance, thermogravimetric analysis, H2-temperature programmed reduction, transmission electro microscopy, and inductively coupled plasma-optical emission spectrometry. IRMOF-3-LA-Au acted as an efficient heterogeneous catalyst in the synthesis of propargylamines by three-component coupling reaction of aldehyde, alkyne, and amine. Moreover, the catalyst is applicable to various substituted substrates, including aromatic and aliphatic aldehydes, alkyl- and aryl-substituted terminal alkynes, and alicyclic amines. In addition, the catalyst can be easily separated from the mixture and can be reused for four consecutive cycles.


Estimating the cost of improving service quality in water supply: A shadow price approach for England and wales.
Service quality to customers is an aspect that cannot be ignored in the performance assessment of water companies. Nowadays water regulators introduce awards or penalties to incentivize companies to improve service quality to customers when setting prices. In this study, the directional distance function is employed to estimate the shadow prices of variables indicating the lack of service quality to customers in the water industry i.e., written complaints, unplanned interruptions and properties below the reference level. To calculate the shadow price of each undesirable output for each water company, it is needed to ascribe a reference price for the desirable output which is the volume of water delivered. An empirical application is carried out for water companies in England and Wales. Hence, the shadow price of each undesirable output is expressed both as a percentage of the price of the desirable output and in pence per cubic meter of water delivered The estimated results indicate that on average, each additional written complaint that needs to be dealt with by the water company includes a service quality cost of 0.399p/m(3). As expected, when looking at the other service quality variables which involve network repair or replacement, these values are considerably higher. On average, the water company must spend an extra 0.622p/m(3) to prevent one unplanned interruption and 0.702p/m(3) to avoid one water pressure below the reference level. The findings of this study are of great importance for regulated companies and regulators as it has been illustrated that improvements in the service quality in terms of customer service could be challenging and therefore ongoing investments will be required to address these issues.


Increasing and sustaining diabetic retinopathy screening in Fiji by leveraging community health workers (CHWs) services: A qualitative study.
Inequities in access to diabetic retinopathy (DR) services particularly in rural and remote Fiji is concerning. This is because DR when left undiagnosed and untreated for long, can lead to vision loss and permanent blindness. Appropriate channels must be explored to strengthen services and ensure equitable access to healthcare for everyone. This study describes the development and implementation of DR awareness training for community health workers (CHWs) and their subsequent engagement to raise awareness and scale-up DR screening for communities throughout Fiji. As part of a programme to reduce the incidence of avoidable blindness due to diabetes amongst people living in the Pacific, DR training for primary level nurses was developed and implemented. As these primary level nurses were already inundated by clinical duties and competing health priorities, a shifting of the task was proposed to engage the CHWs who would instead educate communities on diabetes and DR and make referrals for DR screening. A one-day DR awareness training was developed and implemented by the Pacific Eye Institute with funding from the Fred Hollows Foundation New Zealand. At the end of the DR programme in 2019, the team had achieved their target and trained a total of 823 CHWs giving an 81.32% coverage of the total 1012 registered CHW in the MHMS register. Anecdotal evidence showed a spike in DR referrals and screenings recorded at health facilities. Three key themes emerged related to the involvement of CHWs which include engagement of CHWs, benefits of the engagement, and health system-related challenges. The use of CHWs who are already integrated into the health system was considered a sustainable intervention to strengthen diabetes and DR services at the primary level of care, particularly if it involves community awareness, health education, and health services facilitation The future of the CHWs will depend on their being integrated more systematically into local health services with strengthened management and supervision.


"Greek KOOS-Child: a valid, disease specific, diagnostically accurate and responsive PROM in children with knee-related pathology".
The Knee Injury Osteoarthritis Outcome Score (KOOS)-Child questionnaire is one of the frequently child-friendly measures used in pediatric studies. The aim of this study was to transculturally adapt the Greek version of KOOS-Child and evaluate its clinimetric properties in children with knee disorders. Children visiting the Outpatients Orthopaedic Clinic of a Greek Paediatric General Hospital were considered eligible if they were aged 8-14 years, had a knee soft tissue injury and associated physical limitations. The transcultural adaptation was based on a multistage backward translation approach. Participants completed the KOOS-Child at their first visit to the orthopedic specialist (baseline), 2 weeks and 3 months after baseline. Content validity of the KOOS-Child was evaluated using general QoL measures (KIDSCREEN and Kid-KINDL) and construct validity was explored by correlating relevant items. Responsiveness was evaluated according to the children's response on the given orthopeadic treatment. Sample consisted of 59 children (30 males), aged: 11 ± 1.8 years. The KOOS-Child showed high internal consistency (Cronbach's a: 0.80-0.96). Adequate convergent validity with > 75% relevant a priori hypotheses was confirmed. Construct validity was moderate to strong (Pearson's r correlations between related KOOS and Kid-KINDL subdimensions: 0.54-0.62). KOOS and KIDSCREEN subdimensions correlations were fair (Pearson's r correlations: 0.32-0.65). KOOS-Child's diagnostic accuracy was high. Factor analysis extracted height factors accounting for 76.15% of the total variance, confirmed by the scree plot. Responsiveness was moderate to high with Cohen's d from 0.6 to 1.4. The Greek version of the KOOS-Child demonstrated excellent internal consistency, good construct validity, diagnostic accuracy and interpretability as well as good responsiveness. The measure could be used across Greek children with orthopaedic knee problems. Generalisability of findings is limited due to the relatively limited cohort. II.


Changes in carotid arterial wall viscosity and carotid arterial stiffness in type 2 diabetes patients.
Changes in arterial wall viscosity (AWW) and stiffness during type 2 diabetes (T2D) have been little investigated. We explored changes in carotid AWV considering change in arterial stiffness and loading conditions, in patients with T2D. This cross-sectional, monocentric study compared 19 middle-aged patients with T2D to 30 non-diabetic (ND) controls. The absolute viscosity (WV) was determined as the area of the pressure-lumen cross-sectional area (P-LCSA) loop obtained by carotid tonometry and contralateral echo-tracking. The relative viscosity was determined as the ratio between WV and the elastic energy stored within the arterial wall (WV/WE). Carotid geometry, midwall stress, distensibility and elastic modulus were also compared between groups. T2D patients were older and more frequently had hypertension. Internal diameter, mean central and pulse blood pressure were higher in T2D patients but midwall stress was similar compared to ND controls. WV and WV/WE were higher in T2D patients when compared with ND controls (23 [16-41] vs. 11 [7-18] mm Hg.mm2, p=0.007 and 21% [17-25] vs. 12% [8-17], p < 0.001 respectively) even after adjustment on confounding factors. Carotid arterial stiffness was higher in T2D patients, but after adjustment this difference was only observed for the highest levels of midwall stress. Carotid AWV and stiffness are increased in T2D patients but only AWV is significantly increased after considering loading conditions. Whether this increase in energy dissipation within the arterial wall contributes to alter cardiovascular coupling in T2D remains to be established.


Olfactory function following nasal surgery: a 1-year follow-up.
Olfactory dysfunction is a frequent symptom of nasal and sinunasal disease. Many of these patients undergo nasal sinus or nasal septum surgery. In this study, we evaluated the benefit of nasal surgery on olfactory function over a period of 12 months. Patients included in this study underwent either nasal sinus or nasal septum surgery. All patients were tested for olfactory function using the "Sniffin' sticks" 16 item odor identification test. In addition, patients were asked to rate their nasal patency as well as their olfactory function at each visit. 157 patients were tested 3.5 months after surgery and 52 patients were tested again 12 months after surgery. Olfactory function improved significantly 3.5 months after surgery in patients, who received nasal sinus surgery; no significant increase was found in patients treated with nasal septum surgery. At the 12-month follow-up, the increase in olfactory function over all patients just missed statistical significance. Individually, however, 19% of the patients exhibited improvement after 3.5 months and 17% after 12 months. These numbers increased in patients with rhinosinusitis with nasal polyps, who exhibited improvement of 30% after 3.5 months, and 32% after 12 months. Nasal sinus surgery produced an increase in measured olfactory function, but not nasal septum surgery. This increase appeared to be stable over the examined period of 12 months.


Pollution zone identification research during ozone pollution processes.
Identifying an ozone pollution zone during the pollution processes is significant for ozone pollution management and environmental health risk assessment. However, few studies have focused on ozone pollution zone identification during pollution processes. A spatial-temporal clustering framework for identifying pollution zones during ozone pollution processes was initially proposed in this study, and an ozone pollution process in China in May 2017 was selected as a case. The results showed that the framework can help selecting one more accurate method to identify the pollution zone according to the pollution characteristics of air pollution process. In addition, different ozone pollution zone identification methods work well in different scenarios: The self-organizing map (SOM) method was suitable for identifying the zone with the duration of pollution between 24 and 48 h, the image fusion based on wavelet transform (IFbWT) method for the zone with the duration of pollution over 48 h and the Apriori method for the zone with obvious boundaries between high-value and low-value ozone concentrations. The proposed procedure can also be applied to identify the pollution zone of the pollution process of other pollutants.


Expression of beta-preprotachykinin mRNA and tachykinins in rat dorsal root ganglion cells following peripheral or central axotomy.
The changes in gene expression and protein synthesis induced in neurons by axotomy usually lead to increased production of axon constituents and decreased production of molecules related to neurotransmission. Exceptions to this generalization occur, however, and it is unclear whether the injury itself changes the pattern of synthesis or whether individual mechanisms regulate the synthesis of the various axonal components. We used in situ hybridization histochemistry and immunocytochemistry to compare the changes in L4 and L5 rat dorsal root ganglion neuron levels of preprotachykinin mRNA and tachykinin peptides caused by sciatic nerve injury with those caused by dorsal root injury. Both lesions elicit regeneration, although only the axotomized peripheral processes re-establish functional contact with their targets. In the contralateral, intact dorsal root ganglia approximately 17% of neurons contained detectable levels of both mRNAs and peptides. Sciatic nerve section decreased by 70% the number of neurons labeled for preprotachykinin mRNA at three days post-operatively. Not all cells in the ganglion are axotomized by the sciatic nerve lesion; grain counts over the cells spared by the lesion showed an increased level of labeling, possibly a result of collateral sprouting by these spared cells. By two weeks, the number of cells labeled for preprotachykinin mRNA had decreased to 80% of control levels. The numbers of neurons labeled for tachykinin peptides decreased more slowly and reached approximately 50% of control numbers at two weeks. By six months post-operatively, when regeneration is largely complete, the number of neurons containing both mRNAs and peptides returned to normal. In contrast, dorsal root section did not elicit a decrease in the number of neurons labeled either for the mRNAs or the peptides at any of the post-operative intervals examined. These results indicate that axotomy is not the stimulus that elicits changes in the expression of genes coding for tachykinins. Evidence is considered indicating that interruption of the supply of peripherally derived nerve growth factor may be responsible for the changes in gene expression for tachykinins after axotomy.


Development of sporozoite vaccines for malaria.
Various candidate sporozoite vaccines have been produced and tested. These have been produced by genetic engineering techniques and by polypeptide synthesis. The immunity produced by these synthetic vaccines is mediated by antibody and weak. The antibody levels achieved in human volunteer tests were similar to those resulting form natural infection. Immunity resulting from immunization with irradiated sporozoites is multifactorial. It includes reaction to malaria antigens on infected hepatocytes and it has cell-mediated components; the synthetic vaccines do not induce such reactions. Genetic restriction of cell-mediated immune responses may also limit the utility of synthetic vaccines. Development of an effective vaccine to prevent malaria will not be accomplished easily.


Interindividual variability of lithium-induced EEG changes in healthy volunteers.
A placebo-controlled, double-blind study on the effects of lithium on the electroencephalogram (EEG) was performed in 20 healthy volunteers. A reanalysis of the data which previously had been evaluated by factor analysis and other techniques is presented. The aim of this reanalysis is a quantitative reconstruction of visually defined vigilance stages. In 8 of the 10 healthy subjects who received lithium, a "stabilization" of vigilance on a slightly lowered level (i.e., increased continuity of alpha activity and a tendency in the direction of increased alpha anteriorization) could be demonstrated after a 2-week medication period (mean lithium plasma level: 0.65 mmol/l), indicating that in these subjects lithium counteracts the physiological decline of vigilance to be expected under resting conditions. The interpretation of this finding as a reduction of physiological variability, or as a "dynamic restriction," corresponds to findings in other areas of lithium research which can be interpreted in an analogous manner. In two subjects, however, a small decline of vigilance was observed. These two subjects showed an especially pronounced alpha rhythm in their predrug EEG compared with the other volunteers. The authors discuss whether the delineation of different EEG reaction types contributes to the responder problem in lithium research.


DDT-susceptibility status of malaria vector Anopheles balabacensis balabacensis Baisas (Diptera : Culicidae) in Bangladesh.
DDT-susceptibility tests on Anopheles balabacensis balabacensis Baisas carried out during several years especially during 1979 and 1980 in Sylhet district have been reported. The LC50 value for 1980 was found to be 0.88 +/- S.E. 0.02 showing 2.38 fold increase of tolerance from 1970 (LC50 = 0.37 +/- S.E. 0.07). The species is still found to be susceptible to DDT in Bangladesh. The implication of the use of DDT in controlling malaria due to this species is also discussed.


Senescence Inflames the Pancreatic Tumor Microenvironment.
Pancreatic adenocarcinomas (PDACs) are scarcely vascularized and thus virtually insensitive to chemotherapy and immunotherapy. In a recent issue of Cell, Lowe and collaborators1 have demonstrated that senescence induction by MEK plus CDK4/CDK6 inhibitors favors PDAC revascularization coupled to infiltration by therapeutically actionable CD8+ T cells.


Long-term follow-up after purine analogue therapy in hairy cell leukaemia.
Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.


Ethanol tolerance and synaptic plasticity.
Current concepts of the mechanisms underlying many of the pharmacological effects of ethanol on the CNS involve disruption of ion channel function via the interaction of ethanol with specific hydrophobic sites on channel subunit proteins. Of particular clinical importance is the development of tolerance and dependence to ethanol, and it is likely that adaptive changes in synaptic function in response to ethanol's actions on ion channels play a role in this process. In this article, Judson Chandler, Adron Harris and Fulton Crews discuss potential mechanisms of ethanol-induced changes in synaptic function that might provide a cellular basis for ethanol tolerance and dependence. It is proposed that multiple mechanisms are involved that include both transcriptional and post-translational modifications in NMDA and GABAA receptors.


Comparative in vivo and in vitro study of the cardiac effects of midalcipran and imipramine.
Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug. In anaesthetised guinea-pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50 evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. In in vitro studies on guinea-pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction of Vmax was significant at 3 X 10(-6) M for imipramine and 1 X 10(-5) M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1 X 10(-5) M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90). The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.


Plasma concentrations of soluble TNF-alpha receptors in obese subjects.
Recent studies show an increased adipose production of tumor necrosis factor-alpha (TNF-alpha) in human obesity. It was hypothesized from this finding and other data, that TNF-alpha may be a mediator of obesity-linked insulin resistance. The aim of this study was to measure plasma concentrations of the two soluble TNF-alpha receptors, together with those of TNF-alpha in subjects with severe obesity with and without type 2 diabetes mellitus, in comparison to a lean control group, to examine whether plasma concentrations reflect an up-regulation of the TNF system in adipose tissue. Plasma concentrations of the two soluble TNF-alpha receptors were measured in 49 obese subjects (mean body mass index (BMI): 44.9 kg/m2, 95% confidence intervals (CI) 42.3-47.5 kg/m2, including 19 type 2 diabetic individuals) and 28 lean controls, by using a highly sensitive enzyme-linked immunoassay (ELISA) technique. TNF-alpha concentrations were determined in 28 obese (10 with diabetes) and 23 lean subjects. The obese subjects showed significantly higher plasma concentrations of the soluble p60 and p80 TNF receptor, respectively, compared to the lean control group, independent of the presence of diabetes. Multiple regression analysis, with the p80 TNF receptor as dependent variable, revealed that BMI and log insulin significantly affected the plasma concentration of this soluble receptor subtype, explaining 46% of the variance, whereas for the p60 TNF receptor, only BMI turned out to influence plasma concentrations. TNF-alpha plasma concentrations were not different between the three groups (Kruskal-Wallis test: P=0.34), but due to the low power of the test, an effect of obesity on TNF-alpha is not excluded. These data indicate that plasma concentrations of both soluble TNF receptors are elevated in obesity and insulin resistance, possibly as a function of excess body fat. The reported adipose overexpression of TNF-alpha does not seem to be reflected by elevated plasma concentrations, suggesting a primarily local role of the cytokine.


Cancer and sphingolipid storage disease therapy using novel synthetic analogs of sphingolipids.
Sphingolipid metabolites have become recognized for their participation in cell functions and signaling events that control a wide array of cellular activities. Two main sphingolipids, ceramide and sphingosine-1-phosphate, are involved in signaling pathways that regulate cell proliferation, apoptosis, motility, differentiation, angiogenesis, stress responses, protein synthesis, carbohydrate metabolism, and intracellular trafficking. Ceramide and S1P often exert opposing effects on cell survival, ceramide being pro-apoptotic and S1P generally promoting cell survival. Therefore, the conversion of one of these metabolites to the other by sphingolipid enzymes provides a vast network of regulation and provides a useful therapeutic target. Here we provide a survey of the current knowledge of the roles of sphingolipid metabolites in cancer and in lipid storage disease. We review our attempts to interfere with this network of regulation and so provide new treatments for a range of diseases. We synthesized novel analogs of sphingolipids which inhibit the hydrolysis of ceramide or its conversion to more complex sphingolipids. These analogs caused elevation of ceramide levels, leading to apoptosis of a variety of cancer cells. Administration of a synthetic analog to tumor-bearing mice resulted in reduction and even disappearance of the tumors. Therapies for sphingolipid storage diseases, such as Niemann-Pick and Gaucher diseases were achieved by two different strategies: inhibition of the biosynthesis of the substrate (substrate reduction therapy) and protection of the mutated enzyme (chaperone therapy). Sphingolipid metabolism was monitored by the use of novel fluorescent sphingolipid analogs. The results described in this review indicate that our synthetic analogs could be developed both as anticancer drugs and for the treatment of sphingolipid storage diseases.


A Clinical Decision Rule to Identify Emergency Department Patients at Low Risk for Acute Coronary Syndrome Who Do Not Need Objective Coronary Artery Disease Testing: The No Objective Testing Rule.
We derive a clinical decision rule for ongoing investigation of patients who present to the emergency department (ED) with chest pain. The rule identifies patients who are at low risk of acute coronary syndrome and could be discharged without further cardiac testing. This was a prospective observational study of 2,396 patients who presented to 2 EDs with chest pain suggestive of acute coronary syndrome and had normal troponin and ECG results 2 hours after presentation. Research nurses collected clinical data on presentation, and the primary endpoint was diagnosis of acute coronary syndrome within 30 days of presentation to the ED. Logistic regression analyses were conducted on 50 bootstrapped samples to identify predictors of acute coronary syndrome. A rule was derived and diagnostic accuracy statistics were computed. Acute coronary syndrome was diagnosed in 126 (5.3%) patients. Regression analyses identified the following predictors of acute coronary syndrome: cardiac risk factors, age, sex, previous myocardial infarction, or coronary artery disease and nitrate use. A rule was derived that identified 753 low-risk patients (31.4%), with sensitivity 97.6% (95% confidence interval [CI] 93.2% to 99.5%), negative predictive value 99.6% (95% CI 98.8% to 99.9%), specificity 33.0% (95% CI 31.1% to 35.0%), and positive predictive value 7.5% (95% CI 6.3% to 8.9%) for acute coronary syndrome. This was referred to as the no objective testing rule. We have derived a clinical decision rule for chest pain patients with negative early cardiac biomarker and ECG testing results that identifies 31% at low risk and who may not require objective testing for coronary artery disease. A prospective trial is required to confirm these findings.


Extraction of discriminative features from EEG signals of dyslexic children; before and after the treatment.
Dyslexia is a neurological disorder manifested as difficulty reading and writing. It can occur despite adequate instruction, intelligence, and intact sensory abilities. Different electroencephalogram (EEG) patterns have been demonstrated between dyslexic and healthy subjects in previous studies. This study focuses on the difference between patients before and after treatment. The main goal is to identify the subset of features that adequately discriminate subjects before and after a specific treatment plan. The treatment consists of Transcranial Direct Current Stimulation (tDCS) and occupational therapy using the BrainWare SAFARI software. The EEG signals of sixteen dyslexic children were recorded during the eyes-closed resting state before and after treatment. The preprocessing step was followed by the extraction of a wide range of features to investigate the differences related to the treatment. An optimal subset of features extracted from recorded EEG signals was determined using Principal Component Analysis (PCA) in conjunction with the Sequential Floating Forward Selection (SFFS) algorithm. The results showed that treatment leads to significant changes in EEG features like spectral and phase-related EEG features, in various regions. It has been demonstrated that the extracted subset of discriminative features can be useful for classification applications in treatment assessment. The most discriminative subset of features could classify the data with an accuracy of 92% with SVM classifier. The above result confirms the efficacy of the treatment plans in improving dyslexic children's cognitive skills.


Towards advanced simultaneous nitrogen removal and phosphorus recovery from digestion effluent based on anammox-hydroxyapatite (HAP) process: Focusing on a solution perspective.
In this paper, the state-of-the-art information on the anammox-HAP process is summarized. The mechanism of this process is systematically expounded, the enhancement of anammox retention by HAP precipitation and the upgrade of phosphorus recovery by anammox process are clarified. However, this process still faces several challenges, especially how to deal with the ∼ 11% nitrogen residues and to purify the recovered HAP. For the first time, an anaerobic fermentation (AF) combined with partial denitrification (PD) and anammox-HAP (AF-PD-Anammox-HAP) process is proposed to overcome the challenges. By AF of the organic impurities of the anammox-HAP granular sludge, organic acid is produced to be used as carbon source for PD to remove the nitrogen residues. Simultaneously, pH of the solution drops, which promotes the dissolution of some inorganic purities such as CaCO3. In this way, not only the inorganic impurities are removed, but the inorganic carbon is supplied for anammox bacteria.


Neglected burden of injuries in Ethiopia, from 1990 to 2019: a systematic analysis of the global burden of diseases study 2019.
The 2030 agenda for sustainable development goals has given injury prevention new attention, including halving road traffic injuries. This study compiled the best available evidence on injury from the global burden of diseases study for Ethiopia from 1990 to 2019. Injury data on incidence, prevalence, mortality, disability-adjusted life years lost, years lived with disability, and years of life lost were extracted from the 2019 global burden of diseases study for regions and chartered cities in Ethiopia from 1990 to 2019. Rates were estimated per 100,000 population. In 2019, the age-standardized rate of incidence was 7,118 (95% UI: 6,621-7,678), prevalence was 21,735 (95% UI: 19,251-26,302), death was 72 (95% UI: 61-83), disability-adjusted life years lost was 3,265 (95% UI: 2,826-3,783), years of live lost was 2,417 (95% UI: 2,043-2,860), and years lived with disability was 848 [95% UI: (620-1,153)]. Since 1990, there has been a reduction in the age-standardized rate of incidence by 76% (95% UI: 74-78), death by 70% (95% UI: 65-75), and prevalence by 13% (95% UI: 3-18), with noticeable inter-regional variations. Transport injuries, conflict and terrorism, interpersonal violence, self-harm, falls, poisoning, and exposure to mechanical forces were the leading causes of injury-related deaths and long-term disabilities. Since 1990, there has been a decline in the prevalence of transport injuries by 32% (95% UI: 31-33), exposure to mechanical forces by 12% (95% UI: 10-14), and interpersonal violence by 7.4% (95% UI: 5-10). However, there was an increment in falls by 8.4% (95% UI: 7-11) and conflict and terrorism by 1.5% (95% UI: 38-27). Even though the burden of injuries has steadily decreased at national and sub-national levels in Ethiopia over the past 30 years, it still remains to be an area of public health priority. Therefore, injury prevention and control strategies should consider regional disparities in the burden of injuries, promoting transportation safety, developing democratic culture and negotiation skills to solve disputes, using early security-interventions when conflict arises, ensuring workplace safety and improving psychological wellbeing of citizens.


Phytofabricated silver nanoparticles of Phyllanthus emblica attenuated diethylnitrosamine-induced hepatic cancer via knock-down oxidative stress and inflammation.
Oxidative stress and inflammation play a pivotal role in the expansion and progression of hepatic cancer. Nanoparticle-based drug delivery can quickly enhance the restorative capability of hepatic cancer. Silver nanoparticles synthesized from plant source are of great importance due to their small size, economic, non-hazardous and different biomedical applications. In the current study, we have evaluated the impacts of oxidative stress and proinflammatory markers of biosynthesized silver nanoparticles of Phyllanthus emblica (PE) leaves against diethylnitrosamine-induced hepatocellular carcinoma (HCC) in wistar rats till 16 weeks with its underlying mechanism. The physico-chemical properties of biosynthesized silver nanoparticles were determined by ultra-visible spectroscopy, Fourier transform infrared spectroscopy, field emission scanning electron microscope, energy dispersive X-ray analysis, transmission electron microscopy and X-ray diffraction studies. Biofabricated silver nanoparticles (PEAgNPs) significantly enhanced the process of recovery from hepatic cancer in animal models, which was ascertained by increased body weight, reduced hepatic knobs on the outer surface of liver, downregulated serum biochemical parameters (ALT: 134.66 ± 2.60; AST: 120.33 ± 3.18; ALP: 153.33 ± 4.25; AFP: 167.33 ± 3.38), decreased hepatic lipid peroxidation (20.22 ± 1.74), increased membrane-bound enzymes (Na+/K+ATPase: 4.18 ± 0.20; Ca2+ATPase: 6.24 ± 0.12), increased antioxidants parameters (CAT: 64.89 ± 4.13; SOD: 6.01 ± 0.11; GPx: 8.55 ± 0.05), alteration in the level of proinflammatory cytokines (TNF-α: 90.15 ± 5.77; NF-κB: 173.29 ± 7.26; IL-6: 178.11 ± 3.16; IL-1β: 48.26 ± 1.89) and histopathological studies. Our outcomes implicate successfully biofabrication of silver nanoparticles and exhibited a chemoprotective potential in the prevention and intervention of hepatocellular carcinoma.


Quantitative heteroduplex analysis for single nucleotide polymorphism genotyping.
High-resolution melting of polymerase chain reaction (PCR) products can detect heterozygous mutations and most homozygous mutations without electrophoretic or chromatographic separations. However, some homozygous single nucleotide polymorphism (SNPs) have melting curves identical to that of the wild-type, as predicted by nearest neighbor thermodynamic models. In these cases, if DNA of a known reference genotype is added to each unknown before PCR, quantitative heteroduplex analysis can differentiate heterozygous, homozygous, and wild-type genotypes if the fraction of reference DNA is chosen carefully. Theoretical calculations suggest that melting curve separation is proportional to heteroduplex content difference and that the addition of reference homozygous DNA at one seventh of total DNA results in the best discrimination between the three genotypes of biallelic SNPs. This theory was verified experimentally by quantitative analysis of both high-resolution melting and temperature-gradient capillary electrophoresis data. Reference genotype proportions other than one seventh of total DNA were suboptimal and failed to distinguish some genotypes. Optimal mixing before PCR followed by high-resolution melting analysis permits genotyping of all SNPs with a single closed-tube analysis.


Clinical chorioamnionitis is not predicted by an ultrasonic biophysical profile in patients with premature rupture of membranes.
A modified biophysical profile was assessed serially in 47 patients with premature rupture of membranes who were not in labor. This profile included fetal movement, fetal tone, fetal breathing, amniotic fluid volume, and placental grade. The most recent study, obtained within 2 days of delivery, was compared with pregnancy outcome as reflected by the development of chorioamnionitis and/or neonatal sepsis. No study patient received antibiotics, steroids, or tocolytics before labor. Neither the composite biophysical profile nor any of its components were found to be different between patients with and without clinical chorioamnionitis. Neonatal sepsis was not observed. These data do not support the use of the biophysical profile as a predictor of maternal infection.


Evaluation of intestinal absorption into the portal system in enterohepatic circulation by measuring the difference in portal-venous blood concentrations of diclofenac.
We evaluated the first-pass effects in vivo by the intestine and liver during enterophepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal-venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal-venous blood concentration difference). No portal-venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal-venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Approximately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (FH) of diclofenac was estimated to be 63%.


Modeling temporal dynamics of genetic diversity in stage-structured plant populations with reference to demographic genetic structure.
Predicting temporal dynamics of genetic diversity is important for assessing long-term population persistence. In stage-structured populations, especially in perennial plant species, genetic diversity is often compared among life history stages, such as seedlings, juveniles, and flowerings, using neutral genetic markers. The comparison among stages is sometimes referred to as demographic genetic structure, which has been regarded as a proxy of potential genetic changes because individuals in mature stages will die and be replaced by those in more immature stages over the course of time. However, due to the lack of theoretical examination, the basic property of the stage-wise genetic diversity remained unclear. We developed a matrix model which was made up of difference equations of the probability of non-identical-by-descent of each life history stage at a neutral locus to describe the dynamics and the inter-stage differences of genetic diversity in stage-structured plant populations. Based on the model, we formulated demographic genetic structure as well as the annual change rate of the probability of non-identical-by-descent (denoted as η). We checked if theoretical expectations on demographic genetic structure and η obtained from our model agreed with computational results of stochastic simulation using randomly generated 3,000 life histories. We then examined the relationships of demographic genetic structure with effective population size Ne, which is the determinants of diversity loss per generation time. Theoretical expectations on η and demographic genetic structure fitted well to the results of stochastic simulation, supporting the validity of our model. Demographic genetic structure varied independently of Ne and η, while having a strong correlation with stable stage distribution: genetic diversity was lower in stages with fewer individuals. Our results indicate that demographic genetic structure strongly reflects stable stage distribution, rather than temporal genetic dynamics, and that inferring future genetic diversity solely from demographic genetic structure would be misleading. Instead of demographic genetic structure, we propose η as an useful tool to predict genetic diversity at the same time scale as population dynamics (i.e., per year), facilitating evaluation on population viability from a genetic point of view.


Contrast-enhanced computed tomography radiomics and multilayer perceptron network classifier: an approach for predicting CD20+ B cells in patients with pancreatic ductal adenocarcinoma.
To develop and validate a machine-learning classifier based on contrast-enhanced computed tomography (CT) for the preoperative prediction of CD20+ B lymphocyte expression in patients with pancreatic ductal adenocarcinoma (PDAC). Overall, 189 patients with PDAC (n = 132 and n = 57 in the training and validation sets, respectively) underwent immunohistochemistry and radiomics feature extraction. The X-tile software was used to stratify them into groups with 'high' and 'low' CD20+ B lymphocyte expression levels. For each patient, 1409 radiomic features were extracted from volumes of interest and reduced using variance analysis and Spearman correlation analysis. A multilayer perceptron (MLP) network classifier was developed using the training and validation set. Model performance was determined by its discriminative ability, calibration, and clinical utility. A log-rank test showed that the patients with high CD20+ B expression had significantly longer survival than those with low CD20+ B expression. The prediction model showed good discrimination in both the training and validation sets. For the training set, the area under the curve (AUC), sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 0.82 (95% CI 0.74-0.89), 92.42%, 57.58%, 0.75, 0.69, and 0.88, respectively; whereas these values for the validation set were 0.84 (95% CI 0.72-0.93), 86.21%, 78.57%, 0.83, 0.81, and 0.85, respectively. The MLP network classifier based on contrast-enhanced CT can accurately predict CD20+ B expression in patients with PDAC.


Evaluation of anaerobic membrane bioreactor treating dairy processing wastewater: Elemental flow, bioenergy production and reduction of CO2 emission.
The management of dairy processing wastewater (DPW) must address water pollution while delivering renewable energy and recovering resources. A high-rate anaerobic membrane bioreactor (AnMBR) was investigated for treating DPW, and the system was evaluated in terms of elemental flow, nutrient recovery, energy balance, and reduction of CO2 emission. The AnMBR system was superior in terms of both methanogenic performance and efficiency of bioenergy recovery in the DPW treatment, with a high net energy potential of 51.4-53.2 kWh/m3. The theoretical economic values of the digestate (13.8 $/m3) and permeate (4.1 $/m3) were assessed according to nutrient transformation and price of mineral fertilizer. The total CO2 emission equivalent in the AnMBR was 44.7 kg CO2-eq/m3, with a significant reduction of 54.1 kg CO2-eq/m3 compared to the conventional process. The application of the AnMBR in the DPW treatment is a promising approach for the development of carbon neutrality and a circular economy.


[Cis-platinum in the treatment of disseminated testicular neoplasms resistant to classical chemotherapy].
Seven patients with advanced testicular tumors, resistant to existing chemotheurapeutic agents, were treated with a new antitumor agent, the Cisplatinum (associated to mannitol induced hyperdiuresis). There were 3 objective remissions (1 complete and 2 partial). Major toxicity was gastrointestinal. There was little renal and hematologic toxicity in our serie. The drug may have use in combination therapy in advanced non seminomatous testicular tumors.


Surveillance of Clostridium difficile infections in a long-term care psychogeriatric facility: outbreak analysis and policy improvement.
Following an exceptionally high Clostridium difficile infections (CDI) incidence (Spring 2011) in a psychogeriatric long-term care facility, a bidirectional study (2009-2012) was initiated to identify determinants (retrospectively) and to assess intervention measures taken (prospectively). For every CDI patient (de novo cases, relapses, and recurrences), a control patient (patient in the opposite room) was selected and risk factor analysis performed. Following the epidemic peak a more stringent hygienic protocol and surveillance program were implemented, as well as uniform guidelines for metronidazole and vancomycin prescription. The nutritional state (total protein/prealbumine) significantly differed between the CDI group (poorer nutritional state at admission) and the control group, and also antibiotic use (general) could be confirmed as a risk factor. A multi-disciplinary nutritional team has been established in order to improve the nutritional balance of our patients. Aside from stringent hygiene and antibiotic prescription stewardship, malnutrition of patients is a factor to be taken into account to contain a CDI outbreak in a long term care facility (LTCF).


Negative selection, not receptor editing, is a physiological response of autoreactive thymocytes.
Antigen receptor editing-a process of secondary rearrangements of antigen receptor genes in autoreactive lymphocytes-is a well-established tolerance mechanism in B cells, whereas its role in T cells remains controversial. Here, we investigated this issue using a novel Tcra knock-in locus, which ensured appropriate timing of TCRα expression and allowed secondary rearrangements. Under these conditions the only response to self-antigen that could be unambiguously identified was negative selection of CD4/CD8 double positive thymocytes. No evidence could be obtained for antigen-induced TCR editing, whereas replacement of the transgenic TCRα chain by ongoing gene rearrangement occurred in some cells irrespective of the presence or absence of self-antigen.


Effect of physical training on the development of hypertension in the spontaneously hypertensive rat.
The effect of chronic physical exercise on the development of hypertension was measured in spontaneously hypertensive rats (SHR) and their progenitor normotensive wistar-kyoto controls (WK). Starting 4--5 weeks after birth groups of rats were subjected to swimming exercise 1 h x day-1, 4 days x week-1 for a total period of 11 weeks. Control rats were handled daily without exercise. Both in trained SHR and WK a significant delay in increase in body weight was observed. Physical training caused a small, but significant (P less than 0.001) reduction in systolic blood pressure of SHR, whereas it did not affect blood pressure in WK. Heart rate was significantly (P less than 0.001) lower in both trained SHR and WK than in their non-trained controls. At the end of the training period the degree of training was tested by measuring muscle cytochrome oxidase activity and relative heart weight. Cytochrome oxidase activity in gastrocnemius muscle was higher in the trained animals, although the difference was only significant (P less than 0.05) for WK. Training also caused a significant (P less than 0.01) increase in the ratio heart weight to body weight in WK. Both trained and non-trained SHR have a ca. 25% higher relative heart weight than WK controls. SHR hearts did not further hypertrophy as a consequence of physical exercise. These data indicate that swim training induces a trained state in both SHR and WK. Moreover, this form of training causes a slight, but significant attenuation of the development of hypertension in SHR.


Controlling Valley-Specific Light Emission from Monolayer MoS2 with Achiral Dielectric Metasurfaces.
Excitons in two-dimensional transition metal dichalcogenides have a valley degree of freedom that can be optically manipulated for quantum information processing. Here, we integrate MoS2 monolayers with achiral silicon disk array metasurfaces to enhance and control valley-specific absorption and emission. Through the coupling to the metasurface electric and magnetic Mie modes, the intensity and lifetime of the emission of neutral excitons, trions, and defect bound excitons can be enhanced and shortened, respectively, while the spectral shape can be modified. Additionally, the degree of polarization (DOP) of exciton and trion emission from the valley can be symmetrically enhanced at 100 K. The DOP increase is attributed to both the metasurface-enhanced chiral absorption of light and the metasurface-enhanced exciton emission from the Purcell effect. Combining Si-compatible photonic design with large-scale 2D materials integration, our work makes an important step toward on-chip valleytronic applications approaching room-temperature operation.


Abnormal basement membrane in the inner ear and the kidney of the Mpv17-/- mouse strain: ultrastructural and immunohistochemical investigations.
The loss of the function of the peroxisomal Mpv17-protein and associated imbalanced radical oxygen species (ROS) homeostasis leads to an early onset of focal segmental glomerulosclerosis and sensorineural deafness associated with severe degeneration of cochlear structures. An excessive enlargement of basal laminae of the stria vascularis capillaries and glomeruli indicates numerous changes in their molecular composition. The basement membrane (BM) of the glomeruli and the stria vascularis are simultaneously affected in early stages of the disease and the lamination, splitting of the membrane and formation of the "basket weaving" seen at the onset of the disease in the kidney are similar to the ultrastructural alterations characteristic for Alporta9s syndrome. The progressive alteration of the BMs is accompanied by irregularity in the distribution of the collagen IV subunits and by an accumulation of the laminin B2(gamma1) in the inner ear and B(beta1) in the kidney. Since Mpv17 protein contributes to ROS homeostasis, further studies are necessary to elucidate downstream signaling molecules activated by ROS. These studies explain the cellular responses to missing Mpv17-protein, such as accumulation of the extracellular matrix, degeneration, and apoptosis in the inner ear.


Toxicological sensitivity of protozoa to pesticides and nanomaterials: A prospect review.
Protozoa are sensitive indicators of pollutant toxicity. This review presents and discusses the toxicological studies of protozoa and the toxicological conventional test species (Daphnia magna) by pesticides and nanomaterials, particularly comparing the sensitivity of through relative tolerance analysis, Z-score, and species sensitivity index. The sensitivity of different species of protozoa varies greatly. The protozoa Paramecium sp. and Tetrahymena sp. are not sensitive species; conversely, Urostyla sp. is sensitive to dimethoate and nanomaterials Ag-NPs, respectively ZnO-NPs, and CuO-NPs, fits the use as an indicator species on these substances. The prospects to explore scientific toxicity exposure protocols, expand the protozoan species examined, and screen the sensitive species under the protocols are discussed. This prospect review advances the knowledge for including the sensitive protozoa as an indicator species in comprehensive toxicological analysis for pesticides and nanomaterials.


Intracardiac echocardiography guided radiofrequency catheter ablation of the slow pathway in atrioventricular nodal reentrant tachycardia.
ICE has demonstrated its utility in imaging right atrial structures but its utility in slow pathway (SP) ablation has not been documented in a randomized trial. The feasibility of using ICE as a imaging modality to identify the effective site of SP ablation was done in part one of the study comprising 10 patients of typical AVNRT. Subsequently, a prospective randomized study was done comparing the conventional (group A) and ICE guided (group B) ablation of the SP. Each group had 20 patients of typical AVNRT. Ablation in the conventional arm was guided by intracardiac electrograms and fluoroscopy. Group B patients underwent SP ablation guided primarily by ICE imaging; fluoroscopy was used mainly for initial placement of catheters. Reliable & stable ICE images were obtained in all patients. Part I of the study showed that RF pulses given when the ablation catheter was seen to cross the atrioventricular muscular septum (AVMS), always resulted in junctional rhythm. In Group B, RF pulse was delivered only when the ablation catheter was at the AVMS making an obtuse angle with the image of the His-bundle catheter. Consistent junctional rhythm and abolition of SP resulted at this site. Compared to group A, patients in group B required fewer pulses (mean 1.4 +/- 0.6 vs. 4.4 +/- 3.0; p < 0.05, median 1 vs. 5; p < 0.01), achieved a higher temperature (56 +/- 4 degrees C vs. 50 +/- 6 degrees C) and had more frequent junctional rhythm (100% vs. 70%) during RF pulse. A critical portion of SP exists adjacent to Tricuspid valve overlying the AVMS. ICE imaging consistently and reliably localizes this site and RF applications here result in interruption of antegrade SP conduction.


New Strategies for the Treatment of Older Myeloma Patients.
Multiple myeloma (MM) mostly affects older patients, who represent a highly heterogeneous population. In the last few years, the introduction of novel agents led to a significant improvement in the outcome of MM patients. Nonetheless, this positive trend is less likely to occur in all older patients due to comorbidities/disabilities and major susceptibility to toxic events. Furthermore, older patients with major comorbidities are usually excluded or underrepresented in most registrational clinical trials. In this context, physicians have called for greater caution in the management of the disease. Several scores allow for the identification of frail and unfit patients and establish the possibility of tailoring therapy, reducing toxicity. This review explores the available tools for the assessment of frailty and what has been done to improve the discriminative power of the available scores. Thereafter, it describes the main therapeutic strategies for the management of transplant-ineligible (NTE) newly diagnosed (ND) MM patients and relapsed/refractory (RR) MM patients, in order to better guide physicians in choosing treatment options and to suggest possible strategies for more frail patients.


Taste-to-postingestive consequence conditioning: is the rise in sham feeding with repeated experience a learning phenomenon?
Although the progressive increase in intake with repeated sham feeding experience is assumed to reflect the extinction of learned satiety, the involvement of associative learning in this phenomenon has never been directly demonstrated. We show that: a) animals attenuate sham feeding on initial exposure only with foods tasting like those they have fed normally before, and b) latent inhibition, which retards the formation of CS-US associations in classical conditioning preparations, prevents the association of a taste with its postingestive consequences. These data suggest both that learning plays a role in the development of sham feeding and that associative linking of a food's taste with its postingestive consequences occurs during ingestion. The present results identify properties of taste-to-postingestive consequence conditioning and indicate how the sham feeding preparation can be used to identify the physiological events mediating this learning.


The Regulatory Network Played by miRNAs During Normal Pregnancy and Preeclampsia: A Comparative Study.
Preeclampsia is a pregnancy-specific syndrome, characterized by hypertension, proteinuria, and edema. Affecting between 2% and 8% of gestations worldwide, it accounts for 10% to 15% of maternal deaths. Although its etiology remains unclear, it includes complex pathological processes involving microRNAs, small non-coding RNA molecules with post-transcriptional repression effects on target mRNAs. To assess the expression of miRNAs during normal pregnancies and those complicated by preeclampsia, a sample of Venezuelan women were studied. Nine placental microRNAs (hsa-miR- 20a-5p, 21-3p, 26a-5p, 181a-5p, 199a-5p, 210-3p, 222-5p, 223-3p, 424-3p) were measured in maternal plasma during the second and third trimesters of normal pregnancies, using a SYBR Green®-based real-time PCR, and compared the results against women affected by preeclampsia. All assessed miRNAs were detected in maternal plasma in pregnancies with and without preeclampsia. All except miR-222 were over-expressed during disease when compared to the second and to third-trimester controls. miR-20a, miR-21, miR-26a, and miR-223 were down-regulated in the third trimester in comparison to the second trimester in normal pregnancies. The variation of the miRNAs expression through normal pregnancies suggested their involvement in normal physiological pregnancy processes. In contrast, the significant deregulation of the nine studied miRNAs during preeclampsia indicated the involvement of their target genes in the pathogenesis of the disease. miR-199a and miR-21-3p showed the greatest changes in expression. This study shows for the first time the presence of miR-20a, miR-199, and miR-424 and the variations they undergo in the plasma of pregnant women with preeclampsia.