Analogues of the Inhoffen-Lythgoe diol with anti-proliferative activity.
The anti-proliferative activity of a series of ester- and amide-linked Inhoffen-Lythgoe side chain analogues is reported. Whereas the Inhoffen-Lythgoe diol was inactive in these studies, a number of aromatic and aliphatic ester-linked side chains demonstrated modest in vitro growth inhibition in two human cancepar cell lines, U87MG (glioblastoma) and HT-29 (colorectal adenocarcinoma). Structure-activity relationship (SAR) studies demonstrated the most active aromatic (13) and aliphatic (25 and 29) substituted analogues were approximately equipotent in U87MG and HT-29 cells. Further evaluation of 13, 25, and 29 indicated these analogues do not activate canonical vitamin D signaling nor antagonize Hedgehog (Hh) signaling. Thus, the cellular mechanism(s) that govern the anti-proliferative activity for this class of truncated vitamin D-based structures appears to be different from classical mechanisms previously identified for these scaffolds.


Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems.
Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials. We sought to develop a long-acting, specific GIPR peptide antagonist as a tool compound suitable for investigating GIPR pharmacology in both rodent and human systems. We report a structure-activity relationship of GIPR peptide antagonists based on the human and mouse GIP sequences with fatty acid-based protraction. We assessed these compounds in vitro, in vivo in DIO mice, and ex vivo in islets from human donors. We report the discovery of a GIP(5-31) palmitoylated analogue, [Nα-Ac, L14, R18, E21] hGIP(5-31)-K11 (γE-C16), which potently inhibits in vitro GIP-mediated cAMP generation at both the hGIPR and mGIPR. In vivo, this peptide effectively blocks GIP-mediated reductions in glycemia in response to exogenous and endogenous GIP and displays a circulating pharmacokinetic profile amenable for once-daily dosing in rodents. Co-administration with the GLP-1R agonist semaglutide and this GIPR peptide antagonist potentiates weight loss compared to semaglutide alone. Finally, this antagonist inhibits GIP- but not GLP-1-stimulated insulin secretion in intact human islets. Our work demonstrates the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice.


Electrophysiology of mammalian hypothalamic and interpeduncular neurons in vitro.
Electrical activities of the hypothalamic and interpeduncular neurons were studied in vitro in brain slices prepared from the guinea-pig brain stem. Neurons preserved resting membrane potentials comparable to those of neurons in vivo, responded to stimulation of the afferent fibres, and retained stable spontaneous firings for more than several hours.


Academic technology transfer and radiology: a strong partnership for the future.
To date, technology transfer from academia to industry has been strongest in the biotechnology and pharmaceutical sector. The medical imaging and medical device industries have traditionally been smaller players and, as a result, some, perhaps many, investigators in radiology are unaware of the potential value of technology transfer and the opportunity to receive sponsorship for research from medical imaging companies. Many investigators are also unaware of opportunities to introduce important academic discoveries into clinical practice through licensing and technology transfer. These untapped opportunities are not only valuable, but also are becoming more and more important in light of the ever-increasing difficulties associated with sustaining and receiving new government funding. The goal of this article is to provide academic scientists in the field of radiology with insights about the key aspects of the technology transfer process, including observations about inventions, intellectual property, and industry-sponsored research.


Detailed dosimetric evaluation of intensity-modulated radiation therapy plans created for stage C prostate cancer based on a planning protocol.
Intensity-modulated radiation therapy (IMRT) has been employed as a precision radiation therapy with higher conformity to the target. Although clinical outcomes have been reported for many investigations, detailed treatment planning results have not been mentioned to date. The aim of this study was to evaluate the dose specifications of our IMRT treatment plans for locally advanced prostate cancer. Seventy-seven clinically applied IMRT plans treated between September 2003 and December 2005, in which patients were irradiated with 78 Gy in the prone position, were retrospectively analyzed. Dosimetric data output from dose volume histograms were evaluated in detail. The mean dose ± standard deviation, homogeneity index, and conformity index to the planning target volume (PTV) were 78.3 ± 0.7 Gy (100.4 ± 0.9%), 13.7 ± 3.0, and 0.83 ± 0.04, respectively. For the clinical target volume, the mean dose was 80.3 ± 0.7 Gy (102.9 ± 0.9%).The V40, V60, and V70 Gy of the rectal wall were 58.3 ± 2.8, 29.6 ± 2.7, and 15.2 ± 3.0%, respectively. Planning difficulties were encountered in patients whose bowels were displaced downward, as constraints imposed by the bowel position altered the dose index of the PTV. In many cases, additional bowel optimization parameters were required to satisfy constraints for organs at risk. However, major deviation could be avoided by inverse planning with computer optimization. IMRT allowed the creation of acceptable and practical treatment plans for locally advanced prostate cancer. Reports regarding detailed dosimetric evaluations are mandatory for interpreting clinical outcomes in the future.


Oral antipyretic therapy: evaluation of the N-aryl-anthranilic acid derivatives mefenamic acid, tolfenamic acid and flufenamic acid.
The antipyretic activity of three N-aryl-anthranilic acid derivatives, mefenamic acid, tolfenamic acid and flufenamic acid, was compared and their optimal antipyretic dose determined in a trial in 87 children (aged 5 months to 15 years), who suffered from infections and fever exceeding 38.5 degrees C. Tolfenamic acid proved to be the most potent antipyretic agent of the three drugs; it was eight times more powerful than mefenamic acid and three times more powerful than flufenamic acid. The optimal antipyretic doses were: mefenamic acid 4 mg/kg, tolfenamic acid 0.5 mg/kg and flufenamic acid 1.5 mg/kg. It is evident that the antipyretic activity of these anthranilic acid derivatives is even greater than their antirheumatic effect, the difference being most noticeable in the case of tolfenamic acid.


Heterotypic tetramer (A2D2) complexes of non-epidermal keratins isolated from cytoskeletons of rat hepatocytes and hepatoma cells.
Cytoskeletal residues obtained after extraction of rat liver and cultured rat hepatoma cells (line MH1C1) were used to isolate cytokeratin subunit complexes by solubilization in low salt buffer containing 4 M-urea. Alternatively, the complexes were prepared by solubilization of total cytoskeletal proteins in 9.5 M-urea or 6 M-guanidinium hydrochloride (Gu . HCl), followed by separation using reversed phase high pressure liquid chromatography and dialysis first against either 9.5 M-urea or 6 M-Gu . HCl and then against buffers containing either 4 M-urea or 2 M-Gu . HCl, respectively. The complexes contained only two cytokeratin polypeptides in a 1 : 1 ratio as demonstrated by electrophoresis and isoelectric focusing, i.e. components A (Mr 55,000; isoelectric point in 9.5 M-urea, pH 6.4) and D (Mr 49,000; isoelectric point, pH 5.38) which were separated from each other at urea concentrations higher than 7 M. The complex had a sedimentation coefficient S25,w of 4.96 S in 2 M-Gu . HCl. Sedimentation equilibrium analysis gave an average Mr value of 207,000 which was interpreted as a tetramer containing two chains each of A and D. This complex was also directly demonstrated by gel electrophoresis under non-dissociating conditions. Using dimethyl suberimidate to cross-link the complex in solution of 4 M-urea or 2 M-Gu . HCl, we identified covalently linked heterodimers of A and D, and a tetrameric unit containing equal amounts of A and D which was the largest cross-link product obtained. This complex was similar to the tetrameric complex of rat and human vimentin formed under the same conditions. The constituents of the cross-linked products were identified by two-dimensional ("diagonal") gel electrophoresis, involving the cleavage of the bis(amidine) cross-links after the initial separation in the first dimension. Identical cross-link products were recognized when cytokeratin filaments were used. By electron microscopy the complexes appeared as threads of 2 to 3 nm diameter with a mean length of approximately 48 nm. On dialysis to low salt buffer, the complexes formed 2 to 3 nm protofilaments, intertwisted 3 to 4 nm protofilaments and typical 7 to 11 nm intermediate-sized filaments. Complexes formed from equivalent cytokeratins of other species such as man and cow, as well as heterologous recombinations such as human component A mixed with bovine component D and vice versa, showed the same characteristics.(ABSTRACT TRUNCATED AT 400 WORDS)


Characteristics of infantile convulsions and choreoathetosis syndrome caused by PRRT2 mutation.
Infantile convulsions and choreoathetosis (ICCA) is a rare neurological disorder. Many affected patients are either misdiagnosed or prescribed multiple antiepileptic drugs. To explore therapeutic drug treatments and dosages for ICCA in children. Detailed clinical features (e.g., past medical history and family history), genetic features, and treatment outcomes were collected from the records of six patients with ICCA. Mean age at paroxysmal kinesigenic dyskinesia (PKD) onset was 8 years 8 months (range, 3-12 years); the clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia. All patients had infantile convulsions at less than 1 year of age, and the mean onset age was 5.5 months (range, 4-7 months). Two patients had a family history of ICCA, PKD, or benign familial infantile epilepsy. Whole exome sequencing identified the c.649-650insC mutation in PRRT2 in six patients; three mutations were inherited and three were de novo. All patients were prescribed low-dose carbamazepine and showed dramatic improvement with the complete disappearance of dyskinetic episodes after 3 days. They attended follow-up for 5-17 months and were attack-free until the final follow-up. PRRT2 mutations are the primary cause of ICCA. Low-dose carbamazepine monotherapy is effective and well-tolerated in children.


Coordination of legs during straight walking and turning in Drosophila melanogaster.
Leg coordination of Drosophila melanogaster was studied using frame-by-frame film analysis. 1. For fastest walking alternating tripod coordination is observed which slightly deviates towards tetrapody as a function of step period. During acceleration or deceleration legs may transiently recover in diagonal pairs. 2. Mean step length increases with step frequency. 3. Mean recovery stroke duration increases with step period and plateaus beyond a period of about 110 ms. Middle legs recover significantly faster than others. 4. Ipsilateral footprints are transversally separated. 5. Walking is usually initiated in tripod coordination (frequently in combination with a turn), otherwise in an accelerating sequence which rapidly shifts towards tripod pattern. Flies can stop abruptly or decelerate over about one metachronal wave. 6. Short interruptions in walking are observed. Legs interrupted during swing phase stay lifted and finish recovery thereafter. 7. Slight changes in walking direction are obtained by altering step lengths only. Tight turns are composed of two or three phases with backward, zero and forward translatory components. In fast turning tripod coordination is maintained. Otherwise body sides can decouple widely. In all turns numbers of contralateral metachronal waves were equal. Results are compared to those for other walking insects and their relevance in screens for locomotor mutants is discussed.


Preserving extracellular space for high-quality optical and ultrastructural studies of whole mammalian brains.
Analysis of brain structure, connectivity, and molecular diversity relies on effective tissue fixation. Conventional tissue fixation causes extracellular space (ECS) loss, complicating the segmentation of cellular objects from electron microscopy datasets. Previous techniques for preserving ECS in mammalian brains utilizing high-pressure perfusion can give inconsistent results owing to variations in the hydrostatic pressure within the vasculature. A more reliable fixation protocol that uniformly preserves the ECS throughout whole brains would greatly benefit a wide range of neuroscience studies. Here, we report a straightforward transcardial perfusion strategy that preserves ECS throughout the whole rodent brain. No special setup is needed besides sequential solution changes, and the protocol offers excellent reproducibility. In addition to better capturing tissue ultrastructure, preservation of ECS has many downstream advantages such as accelerating heavy-metal staining for electron microscopy, improving detergent-free immunohistochemistry for correlated light and electron microscopy, and facilitating lipid removal for tissue clearing.


Application of three dimensional printing in surgery for cam type of femoro-acetabular impingement.
Surgical treatment of femoroacetabular impingement (FAI) focuses on improving the clearance for hip motion and alleviation of femoral abutment against the acetabular rim. Cam type of impingement is managed by performing an osteochondroplasty to remove the excess impinging bone from the head neck junction, thus improving the head neck offset. This procedure can be done by safe surgical dislocation, arthroscopy assisted mini-open method or all arthroscopy technique. Whatever be the approach, adequate excision of the Cam deformity is necessary to avoid suboptimal results. Under-excision leads to persistent symptoms and progression of disease, while over-excision can lead to weak bone vulnerable to fracture or disturb the labral seal. Various techniques utilized for intra-operative evaluation of amount of excision required described in literature are fluoroscopy, spherometer gauges, intra-operative Computed Tomography (CT) scan, navigation etc. Rapid prototyping, also called as three dimensional (3D) printing, is a technology to create dimensionally accurate model from a computer-assisted design. Accurate physical models can be designed from the medical imaging data like CT scans and 3D printed to aid in various medical applications. Its application in orthopaedic field is on a rise, recently. However, there is no report on utilization of this technique in surgeries for FAI. We have reported a case of Cam type FAI in an eighteen year old boy, which we treated surgically by performing osteochondroplasty using safe surgical dislocation. We did CT based virtual surgical planning to design femoral head and neck jigs, which were 3D printed and used intra-operatively to guide for adequate and optimum excision of bone at head neck junction. We found these customized jigs accurate and useful for the surgery. However, a comparison study with various other techniques is warranted for a detailed research on its usefulness and challenges. The main purpose of this article is to elaborate on the technical steps for designing of jigs for 3D printing to guide in osteochondroplasty surgery for FAI.


Benign pneumoperitoneum after fiberoptic colonoscopy. A prospective study of 100 patients.
A prospective study of 100 consecutive unselected patients undergoing both diagnostic and therapeutic firoptic colonoscopy was undertaken. Our incidence of colonic perforation is 1%, which is similar to the incidence reported in the literature. This study suggests that even when immediate postcolonoscopic supine and erect abdominal radiographs as well as pre- and postcolonoscopic total blood counts and enzyme levels to supplement clinical impressions are obtained, the incidence of perforation of the colon after fiberoptic colonoscopy is low and not any higher than that reported in the literature. Pneumoperitoneum may occur after fiberoptic colonoscopy with minimal or no clinical evidence suggesting perforation. Perforation in some patients may be treated conservatively without the need of emergency laparotomy.


Selenium depletion and its correction in a child with homocystinuria.
A child of 10 months with proven homocystinuria was found to be selenium depleted and we report the serial monitoring of replacement therapy. Selenium, as an enriched yeast preparation, equivalent to 50 mug on alternate days was required for maintenance. Indices of selenium status returned to normal in varying times. The child initially demonstrated an abnormality of an in vitro challenge by hydrogen peroxide to her erythrocytes, that returned to within normal limits with selenium therapy alone, the serum vitamin E concentration being normal.


Etiology and pathogenesis of oral lichen planus: an overview.
Oral lichen planus is a noninfectious, chronic inflammatory condition that involves the oral mucosal stratified squamous epithelium and the underlying lamina propria and may be accompanied by skin lesions. This overview describes the current understanding of the immunopathologic mechanisms implicated in oral lichen planus.


Modeling human brain rhabdoid tumor by inactivating tumor suppressor genes in induced pluripotent stem cells.
Atypical teratoid/rhabdoid tumor (ATRT) is a rare childhood malignancy that originates in the central nervous system. Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1. ATRT has no standard treatment, and a major limiting factor in therapeutic development is the lack of reliable ATRT models. We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells (Epi-iPSCs), followed by brief neural induction, to generate an ATRT-like model. The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers. High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines. Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids. Nucleophosmin, Osteopontin, and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids. In summary, the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels. Ribociclib, PTC-209, and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells. This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.


Promoter DNA methylation is associated with KLF11 expression in epithelial ovarian cancer.
As a transforming growth factor-β (TGF-β)-inducible gene, the expression of Krüppel-like transcription factor 11 (KLF11) is altered in several types of cancer. In the current study, through using human 9K CpG island array, KLF11 was identified as one of hypermethylated genes in RAS-transformed ovarian T29H cells. Methylation of the KLF11 promoter was also observed in ovarian cancer tissue samples accompanied by significantly reduced KLF11 gene expression. Interestingly, the expression of SMAD2, SMAD3, and SMAD7 genes was reduced in the tumour, whilst no change was found in TGF-β expression. Our data suggest a relationship between promoter DNA methylation and KLF11 gene expression in ovarian cancer tumorigenesis.


A practical data processing workflow for multi-OMICS projects.
Multi-OMICS approaches aim on the integration of quantitative data obtained for different biological molecules in order to understand their interrelation and the functioning of larger systems. This paper deals with several data integration and data processing issues that frequently occur within this context. To this end, the data processing workflow within the PROFILE project is presented, a multi-OMICS project that aims on identification of novel biomarkers and the development of new therapeutic targets for seven important liver diseases. Furthermore, a software called CrossPlatformCommander is sketched, which facilitates several steps of the proposed workflow in a semi-automatic manner. Application of the software is presented for the detection of novel biomarkers, their ranking and annotation with existing knowledge using the example of corresponding Transcriptomics and Proteomics data sets obtained from patients suffering from hepatocellular carcinoma. Additionally, a linear regression analysis of Transcriptomics vs. Proteomics data is presented and its performance assessed. It was shown, that for capturing profound relations between Transcriptomics and Proteomics data, a simple linear regression analysis is not sufficient and implementation and evaluation of alternative statistical approaches are needed. Additionally, the integration of multivariate variable selection and classification approaches is intended for further development of the software. Although this paper focuses only on the combination of data obtained from quantitative Proteomics and Transcriptomics experiments, several approaches and data integration steps are also applicable for other OMICS technologies. Keeping specific restrictions in mind the suggested workflow (or at least parts of it) may be used as a template for similar projects that make use of different high throughput techniques. This article is part of a Special Issue entitled: Computational Proteomics in the Post-Identification Era. Guest Editors: Martin Eisenacher and Christian Stephan.


Efficacy of Postoperative Analgesia by Erector Spinal Plane Block after Lumbar Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
In recent years, erector spinae plane block (ESPB) has been increasingly used as a new regional block technique for postoperative analgesia; however, little is known on its benefits. Therefore, we performed a systematic review and meta-analysis to investigate the efficacy and safety of ESPB in lumbar spine surgery. Databases including PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for randomized controlled trials (RCTs) comparing ESPB with no block in lumbar spine surgery until September 30, 2021. The primary outcome was opioid consumption after surgery. The Cochrane Collaboration's tool for assessing the risk of bias was used to evaluate the quality of included studies. Fifteen RCTs involving 980 patients were included in the study. Opioid consumption 24 hours after surgery was significantly lower in the ESPB group standardized mean difference (SMD = -2.27, 95% confidence interval (95% CI) (-3.21, -1.32); p < 0.01). ESPB reduced pain scores at rest and on movement within 48 hours after surgery and the incidence of the postoperative rescue analgesia (RR = 0.32, 95% CI (0.31, 0.80); p = 0.02), while it significantly prolonged time to first rescue analgesia (SMD = 4.87, 95% CI (2.84, 6.90); p < 0.01). Moreover, significantly better patient satisfaction was associated with ESPB (SMD = 1.89, 95% CI (1.03, 2.74); p < 0.01). EPSB provides effective and safe postoperative analgesia after lumbar spine surgery.


Method validation approach on the basis of a quadratic regression model.
A method validation approach that bases on a quadratic regression model in which two types of error are incorporated is presented and applied to an experimental data set. The validation approach enables the determination of analytical performance characteristics referred to in Commission Decision 2002/657/EC (i.e., repeatability, within-laboratory reproducibility, decision limit, detection capability).


Unconscious, stimulus-dependent priming and conscious, percept-dependent priming with chromatic stimuli.
Using metacontrast masking to suppress the conscious registration of a prime stimulus, Breitmeyer, Ro, and Singhal (2004) showed that color priming produced by a masked prime disk occurs at unconscious stimulus-dependent rather than at percept-dependent levels of visual processing. The current set of experiments compares this type of unconscious stimulus-dependent priming to conscious priming produced by a prime that, in two separate ways, is rendered visible and thus activates percept-dependent visual processes. The results indicate that while the masked prime again acts at a stimulus-dependent level of processing, the unmasked, visible primes additionally act at a later percept-dependent level of processing.


Recovery of virus from the liver of children with fatal dengue: reflections on the pathogenesis of the disease and its possible analogy with that of yellow fever.
Dengue viruses types 2 or 3 were recovered from the liver of 5 out of 17 children who were suspected to have died of dengue. Among the 5 children with liver isolates, virus was also recovered from the heart blood, spleen and midbrain of one and from the spleen of another. Attention is drawn to the many similarities in the clinical manifestations of yellow fever and severe dengue, their indistinguishable liver lesions and the close relationship of the viruses themselves. In view of the liver isolates reported here and those described by others, it is suggested that the pathogenesis of the two diseases may be analogous.


Anal cleansing practices and faecal contamination: a preliminary investigation of behaviours and conditions in schools in rural Nyanza Province, Kenya.
To learn how children in rural schools in Nyando District, Kenya clean themselves after defecation. Six focus group discussions were held with boys and girls ages 12-15 in three rural schools in mid-2009. Parents were interviewed in one setting. In early 2010, a survey of head teachers was conducted in 114 schools in Nyanza Province, Kenya, to assess the provision of anal cleansing materials and handwashing water and soap in schools. Anal cleansing behaviour is linked with access to materials, age, social pressure, perceived personal risk of illness and emotional factors. Materials used for anal cleansing include schoolbook paper, leaves, grasses, stones, corncobs and one's own hands. Students have knowledge gaps in terms of personal hygiene. They were forthcoming with information on their anal cleansing practices. Almost no schools budgeted for or provided anal cleansing materials regularly. Anal cleansing is a necessary human activity. However, because of social taboos, there are few articles on the topic. School health plans overlook it as well. Researchers need to determine if and how current practices could harm child health to inform policy.


A challenging case of COVID-19: a COVID-19 positive adolescent presented with severe diabetic ketoacidosis, resistant hypertension.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus which causes COVID-19. It binds to the angiotensin-converting enzyme 2 (ACE2) receptors, expressed in key metabolic organs and tissues, including pancreatic beta cells, adipose tissue, the small intestine, and kidneys. This condition has been linked to a variety of additional symptoms, including acute encephalopathy, changes in consciousness, and even gastrointestinal bleeding. In this study, we have reported a 13-year-old boy, 69 kg, with SARS-COV-2 infection. In this case, multiple systems, including the endocrine, renal, pulmonary, gastrointestinal, and nervous systems, were affected. It is speculated that different manifestations of COVID-19 can be seen in clinical settings, and practitioners should be more cautious not to miss the chimeric characteristics of COVID-19 infection.


Multiple system organ failure.
Multiple system organ failure represents the final common pathway to a fatal outcome in severely infected patients. Despite the development of extensive support technology, the mortality rate in this group of patients remains high: in excess of 50 per cent. This rate underscores the need for newer treatment modalities. Numerous mediators/effectors appear to play a role in the complex evolution of the process. The independent and interactive effects of these numerous mediators/effectors remain to be elucidated. Future therapies will need to address immunomodulation of the host and biochemical manipulation of the fundamental process before significant improvement in outcome can be expected.


[Rupture of atherosclerotic aneurysms of abdominal aorta into the duodenum].
A woman, 77 years old, and two men aged 65 and 70 years died 28-96 hours after sudden beginning of recurrent massive gastrointestinal hemorrhages of clinically unknown origin. Ruptured atherosclerotic abdominal aortic aneurysms with aortoduodenal fistulas were revealed at autopsies. Anatomical predispositions for these rare complications and the causes of the diagnostic mistakes are discussed.


Principles of creation of protein carriers of DNA new derivatives of human epidermal growth factor for gene therapy.
We formulated a new approach to the creation of transport proteins for the delivery of foreign DNA to target cells and used it for obtaining a polypeptide PGEk. Structural and functional analysis of PGEk--DNA complexes demonstrated good prospects for the creation of a wide spectrum of targeted preparations for gene therapy. These approaches and regularities are necessary for construction of new DNA carriers selective for various cell types.


Conservation of orbital angular momentum and polarization through biological waveguides.
A major roadblock to the development of photonic sensors is the scattering associated with many biological systems. We show the conservation of photonic states through optically self-arranged biological waveguides, for the first time, which can be implemented to transmit light through scattering media. The conservation of optical properties of light through biological waveguides allows for the transmission of high bandwidth information with low loss through scattering media. Here, we experimentally demonstrate the conservation of polarization state and orbital angular momentum of light through a self-arranged biological waveguide, several centimeters long, in a sheep red blood cell suspension. We utilize nonlinear optical effects to self-trap cells, which form waveguides at 532 nm and 780 nm wavelengths. Moreover, we use the formed waveguide channels to couple and guide probe beams without altering the information. The formed biological waveguides are in a sub-diffusive scattering regime, so the photons' information degrades insignificantly over several centimeters of propagation through the scattering media. Our results show the potential of biological waveguides as a methodology for the development of novel photonic biosensors, biomedical devices that require optical wireless communication, and the development of new approaches to noninvasive biomedical imaging.


Comparison of saphenous vein patch, polytetrafluoroethylene patch, and direct arteriotomy closure after carotid endarterectomy. Part I. Perioperative results.
To evaluate the perioperative outcomes and the immediate increases in size after patch closure, 140 carotid endarterectomies were randomized into one of three groups: direct no-patch closure, saphenous vein patch closure, and polytetrafluoroethylene patch closure. Seven patients (4.4%) experienced signs of cerebral ischemia in the immediate postoperative period. In three cases this was transient and reversible. In the other four reexploration was undertaken and carotid thrombosis was corrected by thrombectomy. The condition of one of these patients deteriorated to a permanent stroke, whereas the other patients made a complete recovery. Neurologic complications were more frequent in the no-patch group, but the differences between the groups were not significant. The incidence of perioperative internal carotid stenosis, aneurysmal dilatation, and other morphologic abnormalities was assessed in 131 intravenous digital subtraction angiograms taken before the patient was discharged from the hospital. Eight (17.0%) of the endarterectomies in the no-patch group were narrowed by 30% to 50% diameter stenosis, whereas none of the patched arteries had more than 30% stenosis. In contrast, dilatation of the common or internal carotid artery to more than twice the measured diameter was absent in non-patched arteries but was present in seven (17.0%) saphenous patch closures and four (9.23%) polytetrafluoroethylene patch closures. We conclude that patch closure after carotid endarterectomy is less likely to cause stenosis in the perioperative period. Poly-tetrafluoroethylene patches resist dilatation better than do saphenous vein patches and are less likely to become aneurysmal.


Traumatic thrombosis of a segmental branch of the renal artery.
Traumatic thrombosis of a segmental renal artery branch is being diagnosed with increased frequency because of the more frequent evaluation of renal injury by isotope renography, arteriography or computerized tomography, leading to questions about appropriate management. The medical records of 9 documented cases of segmental thrombosis were reviewed. No specific diagnostic features were found on clinical examination or an initial excretory urogram. All 9 patients had associated injuries (an average of 2.0 per patient) and 2 died of these injuries. One patient had immediate surgical repair of a thrombosed posterior branch of the renal artery whereas the other 8 had nonoperative management. No hypertension was found on followup of the 5 available patients, and hypertension occurred in only 10 of 170 reported cases (6 per cent) of traumatic thrombosis or operative ligation of segmental branches. Traumatic thrombosis of a segmental renal artery branch initially should be managed nonoperatively.


Exposure factors associated with dementia among older adults in Iceland: the AGES-Reykjavik study.
The study aimed to assess whether factors related to cognitive performance were associated with the development of dementia. Additionally, the study aimed to establish whether cognitive performance at baseline or change in cognition between baseline and follow-up (five-year period) had a stronger association with whether an individual would fulfill a dementia criterion at follow-up. The data was collected from 2002 to 2011. Logistic regression was applied to the AGES-Reykjavik Study epidemiological data. The analysis, which builds upon previous data analyses of the same dataset, included 1,491 participants between the ages of 66 and 90. All those included were considered to have normal cognition at baseline; 8.2% (n = 123) of them fulfilled a dementia criterion at follow-up five years later. The study's results indicated that being high on cognitive reserve factors reduced the risk of developing dementia. Compared to other known dementia risk factors, cognitive reserve factors (education level, participation in leisure activities, and self-reported health) were more likely than others to have an association with dementia. Additionally, the study's findings showed that cognitive performance at baseline, rather than change in cognition between baseline and follow-up five years later, had a stronger association with dementia at the follow-up assessment. Together, these findings support the notion that promoting high cognitive reserve throughout the lifespan and reaching high cognitive performance is important in reducing dementia risk.


Aseptic sialadenitis in preterm infants associated with long-term oro-gastric tube feeding.
Sialadenitis is a rare disease in the newborn and the pathogenesis in this age group is not fully understood. We report five cases of neonatal sialadenitis in stable preterm, gavage-fed infants at 2 to 6 weeks postnatal age. The occurrence of sialadenitis was observed in temporal relation to changes in enteral feeding routines in the unit which were initiated with the objective of promoting full breast feeding at discharge. Clinical presentation consisted of a tender palpable mass over one of the salivary glands, low-grade (37.5-38.3 degrees C) fever in conjunction with clinical malaise. C-reactive protein and white blood cell count were only moderately elevated. No suppuration from salivary ducts was present. Bacterial cultures were invariably negative. Viral investigations were not carried out. Aseptic sialadenitis was suggested as the cause of the symptoms. The clinical course was benign and the local tender mass over the salivary gland vanished shortly after intravenous fluids and antibiotics were started. Long-term exclusive oro-gastric feeding may result in reduced reflex salivary gland stimulation, saliva production and hence ductal clearance of mucoid saliva, leading to functional ductal obstruction and local inflammation.


Atrial Cardiopathy and Stroke Prevention.
Many patients with ischemic stroke have a stroke syndrome and neuroimaging findings consistent with embolism, but no evidence of atrial fibrillation. Recent data suggest that the pathological atrial substrate, or atrial cardiopathy, that underlies atrial fibrillation, rather than atrial fibrillation itself, may be an important cause of unexplained strokes. This paper will review the literature on the rationale and data behind the concept of atrial cardiopathy, its pathophysiology, suggested biomarkers of atrial cardiopathy, and therapeutic implications. Several lines of evidence suggest that patients can have strokes associated with disorders of the atrium, even without frank atrial fibrillation. Even in patients with paroxysmal atrial fibrillation, cardiac emboli may occur temporally disassociated from episodes of atrial fibrillation, and the left atrial appendage flow patterns associated with increased thromboembolic risk may occur even when the surface electrocardiogram demonstrates normal sinus rhythm. Biomarkers of left atrial structural and electrophysiological abnormalities have been associated with stroke risk, even in the absence of atrial fibrillation. Atrial cardiopathy, as determined by the presence of biomarkers of left atrial dysfunction, may provide a therapeutic target to reduce the risk of cardioembolic stroke in the absence of atrial fibrillation. Clinical trials are currently ongoing to test this hypothesis.


Application of phosphatidylethanol (PEth) in whole blood in comparison to ethyl glucuronide in hair (hEtG) in driving aptitude assessment (DAA).
For driving aptitude assessment (DAA), the analysis of several alcohol biomarkers is essential for the detection of alcohol intake besides psycho-medical exploration. In Switzerland, EtG in hair (hEtG) is often the only direct marker for abstinence monitoring in DAA. Therefore, the suitability of phosphatidylethanol (PEth) was investigated as additional biomarker. PEth 16:0/18:1 and 16:0/18:2 were determined by online-SPE-LC-MS/MS in 136 blood samples of persons undergoing DAA and compared to hEtG, determined in hair segments taken at the same time. With a PEth 16:0/18:1 threshold of 210 ng/mL for excessive alcohol consumption, all (n = 30) but one tested person also had hEtG values ≥30 pg/mg. In 54 cases, results are not in contradiction to an abstinence as neither PEth (<20 ng/mL) nor hEtG (<7 pg/mg) was detected. In eight cases, both markers showed moderate consumption. Altogether, PEth and hEtG were in accordance in 68 % of the samples, although covering different time periods of alcohol consumption. With receiver operating characteristic analysis, PEth was evaluated to differentiate abstinence, moderate, and excessive alcohol consumption in accordance with hEtG limits. A PEth 16:0/18:1 threshold of 150 ng/mL resulted in the best sensitivity (70.6 %) and specificity (98.8 %) for excessive consumption. Values between 20 and 150 ng/mL passed for moderate consumption, values <20 ng/mL passed for abstinence. As PEth mostly has a shorter detection window (2-4 weeks) than hEtG (up to 6 months depending on hair length), changes in drinking behavior can be detected earlier by PEth than by hEtG analysis alone. Therefore, PEth helps to improve the diagnostic information and is a valuable additional alcohol marker for DAA.


Danshen protects kidney grafts from ischemia/reperfusion injury after experimental transplantation.
Danshen (DS) is used for treatment of various ischemic events in the traditional Chinese medicine. Hence, this study was designed to investigate its effect on ischemia/reperfusion injury (IRI) after experimental kidney transplantation (eKTx). Nephrectomized Sprague-Dawley rats underwent eKTx. Some animals were infused with 1.5 ml DS 10 min before surgery. Kidney grafts were transplanted after cold storage for 20 h in Histidine-Tryptophane-Ketoglutarate solution. After reperfusion blood samples were collected for blood urinary nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and alanine transaminase. Further, tissue was assessed for morphologic and pathophysiologic changes. Donor preconditioning with DS (DS-d) significantly decreased BUN, creatinine, LDH, and aspartate aminotransferase to 65-97% of controls while preconditioning of the recipient (DS-r) decreased values to 58-82% (P < 0.05). Tubular damage and caspase-3 decreased significantly in both DS-d and DS-r (DS-d: 96% and 67%, DS-r: 83% and 75% of controls) while heat shock protein 72 and superoxide dismutase increased significantly (DS-d: 143% and 173%, DS-r: 166% and 194% of controls). Further, inducible nitric oxide synthase and tumor necrosis factor-alpha decreased (DS-d: 84% and 61%, DS-r: 79% and 67% of controls) after DS. Preconditioning of both donors and recipients with DS significantly reduces IRI and thus improves graft function after eKTx.


[Recurrent and recurring inguinal hernias. 50 cases operated upon via a sub-peritoneal approach (author's transl)].
The superiority of this method of hernia repair via a sub-peritoneal approach over classical techniques would seem to have been demonstrated since no failures were noted amongst 50 cases treated. The technique involves the complete resection of the sac of congenital hernias, the complete reduction of the sac of direct or recurring hernias and the abandonment of all sutures in favour of the broad apposition of a plaque which perfectly obliterates the deep orifices of the inguinal region.


[Effect of honey and autologous serum on corneal epithelial healing in rabbits].
To evaluate the efficacy of pure honey and 20% autologous serum and BSS in corneal epithelial healing in rabbits after 48 hours. All solutions were applied after an epithelial removal of 13-millimeters diameter area. Areas of epithelial healing were studied at 12, 24 and 48 hours. The eyes were treated every four hours during 2 days. All treated eyes were assigned to a control group (contralateral eye) treated with a balanced saline solution. All studied groups were not significantly different. In group one, the eyes treated with honey and the control were similar (p<0.87). In the second group the eyes treated with autologous serum and the control presented no difference in the mean score (p<0.072). Corneal epithelial healing in rabbits did not show improvement after application of either honey or autologous serum. It was possible to establish that the autologous serum treated eyes were clinically better than the control group but without statistical significance.


Thyroarytenoid botulinum toxin injection for refractory laryngeal contact granuloma.
Although there are many treatments for laryngeal contact granuloma (LCG), some patients still fail treatment. Botulinum toxin A injection vocal cords may be a salvage therapy. To study the efficacy of thyroarytenoid botulinum toxin A injection for the treatment of refractory LCG. From May 2021 to March 2022, 23 male patients with refractory idiopathic LCG were treated by injection of botulinum toxin A into the thyroarytenoid muscle via the thyrohyoid membrane approach. Inspiratory-phase laryngoscopy images were collected before treatment and 3 months after injection treatment. The lesion size was evaluated with the Farwell granuloma endoscopic grading system and Image J software. The average age of 23 patients was 49 years. The dose of botulinum toxin injection ranged from 2.5 to 5 units. Three months after injection, 17 patients were cured, 2 patients showed marked improvement, and 4 patients did not experience any effect. The total efficacy rate was 82.61% (19/23), and no serious complications occurred. Almost all patients experienced hoarseness within one week after injection; they gradually recovered after one month, and their voice returned to baseline at 3 months. Thyroarytenoid botulinum toxin injection is an effective method for resolving refractory LCG.


The accumulation study of ⁹⁰Sr in fish from a fishpond of northern Taiwan.
Three kinds of fish from a natural fishpond in the north of Taiwan were collected and analyzed in this study. The three species were non-predatory Ctenopharyn odon idellus, predatory Aristichthys nobilis and predatory Mylopharyngodon piceus. The activity concentrations of (90)Sr in bone and edible flesh of fish, as well as in water and soil of fishpond were measured by using the radiochemical analysis. Additionally, the concentration of stable calcium in fish bone, [Ca]bone, and that of stable strontium in fish bone, [Sr]bone, were measured by ICP-AES. From the results, the concentration factors of (90)Sr, CF((90)Sr), in fish bone was no statistic difference between non-predatory and predatory fish. Besides, the accumulation of (90)Sr in the non-predatory fish remarkably decreased with increasing the fish weight. As for the predatory fish, they both showed no statistically significant correlations between the (90)Sr activity concentration and the fish weight. Regarding the activity concentrations of (90)Sr in fish bone, all the fish were observed positively correlated with the measured [Sr]bone.


Comparison of the hemodynamic response of dexmedetomidine versus additional intravenous lidocaine with propofol during tracheal intubation: a randomized controlled study.
Laryngoscopy and tracheal intubation are strong stimuli that cause a reflex increase in blood pressure (BP), heart rate (HR), and serum catecholamine level. These can lead to myocardial infarction or cerebrovascular accidents. The purpose of this study is to compare the efficacy of dexmedetomidine and lidocaine combined with propofol in attenuating the hemodynamic response following laryngoscopy and endotracheal intubation. This study was a randomized controlled study and adhered to the CONSORT guidelines. One-hundred and six patients undergoing elective general anesthesia with endotracheal intubation were divided randomly into two groups. Group D received dexmedetomidine (1 μg kg- 1) before induction. Group LP received lidocaine (1.5 mg kg- 1) before induction with additional propofol (0.5 mg kg- 1) before laryngoscopy. The primary endpoint was hemodynamic including systolic (S) BP, diastolic (D) BP, mean arterial blood pressure (MAP) and HR measured before and after induction and ≤ 10 min after intubation. Secondary outcome was complications/adverse effects. After induction, the mean SBP, DBP, MAP and HR decreased significantly from baseline in both groups except for mean HR in group LP at 1 min. Differences in mean values of SBP, DBP, and MAP were significantly lower in group D after intubation at 4-10 min (P < 0.05). Group LP had a non-inferior effect in blunting BP at all time points except 1 and 2 min after induction, and 2 min after intubation. The mean difference in HR in group D was significantly lower than that in group LP at all time points (P < 0.001). Group D had significantly more episodes of bradycardia (18.87% vs. 0%, P = 0.001) and hypotension (52.83% vs. 15.09%, P < 0.001) than did group LP. Lidocaine (1.5 mg kg- 1) with additional propofol (0.5 mg kg- 1) had a non-inferior effect compared with dexmedetomidine (1 μg kg- 1) in attenuating the hemodynamic response following laryngoscopy and endotracheal intubation, and had fewer adverse effects. Thai Clinical Trial Registry, ( TRTC20190206002 ). Retrospectively registered 4 February 2019.


Corrigendum: Dissecting the Role of N6-Methylandenosine-Related Long Non-Coding RNAs Signature in Prognosis and Immune Microenvironment of Breast Cancer.
[This corrects the article DOI: 10.3389/fcell.2021.711859.].


Length heterogeneity of the rRNA precursor in cucumber (Cucumis sativus).
The length homogeneous part of the intergenic spacer (IGS) of the 18S-25S ribosomal RNA genes of cucumber (Cucumis sativus) was characterized by sequencing 2389 bp preceding the 18S rRNA coding region of a 12.5 kbp repeat type. This part of the IGS is composed of repeated elements and shows a very complex structural organization. Most obvious is a 119 bp element which is repeated seven times. A single transcription initiation site (TIS) was detected by a 'T4 polymerase stop' experiment upstream of these repetitions giving rise to a 2013 bp 5' external transcribed spacer (ETS) for cucumber. Nuclease mapping showed several transcription termination sites (TTS): the first one is located 350 bp downstream of the 25S rRNA coding region, the others are found within the duplications of this region accounting for the length heterogeneity of cucumber rDNA. Therefore, the TTS is repeated two or three times in the IGS depending on the length of the respective repeat classes and the rRNA precursor is heterogeneous in length varying from approx. 8000 to 11000 nts.


Granulocyte transfusion therapy in paediatric patients with severe neutropenic infection.
The data of 10 children who developed 13 high-risk febrile neutropenia with/without microbiologically documented severe infection, while being treated for a hematologic disorder were investigated retrospectively. The 24th hour post-transfusion neutrophil and platelet counts increased significantly, compared to the baseline values (p=0.034, p=0.025). Except three granulocyte transfusions (GTs) after which oliguria and/or mild respiratory distress developed, the transfusions were well tolerated. The clinical response, hematologic response and infection related mortality rates were 69.2%, 53.8% and 30.8%, respectively. Although our study includes limited number of patients, we can conclude that GT seems beneficial for children with severe sepsis during neutropenia.


Computer-Mediated Therapies for Stroke Rehabilitation: A Systematic Review and Meta-Analysis.
To evaluate the efficacy of different forms of virtual reality (VR) treatments as either immersive virtual reality (IVR) or non-immersive virtual reality (NIVR) in comparison to conventional therapy (CT) in improving physical and psychological status among stroke patients. The literature search was conducted on seven databases: ACM Digital Library, Medline (via PubMed), Cochrane, IEEE Xplore, Web of Science, Scopus, and science direct. The effect sizes of the main outcomes were calculated using Cohen's d. Pooled results were used to present an overall estimate of the treatment effect using a random-effects model. A total of 22 randomized controlled trials were evaluated. 3 trials demonstrated that immersive virtual reality improved upper limb activity, function and activity of daily life in a way comparable to CT. 18 trials showed that NIVR had similar benefits to CT for upper limb activity and function, balance and mobility, activities of daily living and participation. A comparison between the different forms of VR showed that IVR may be more beneficial than NIVR for upper limb training and activities of daily life. This study found out that IVR therapies may be more effective than NIVR but not CT to improve upper limb activity, function, and daily life activities. However, there is no evidence of the durability of IVR treatment. More research involving studies with larger samples is needed to assess the long-term effects and promising benefits of immersive virtual reality technology.


Do repeated changes of abutments have any influence on the stability of peri-implant tissues? One-year post-loading results from a multicentre randomised controlled trial.
To evaluate the influence of at least three abutment changes in conventionally loaded implants against placement of a definitive abutment in immediately non-occlusal loaded implants on hard and soft tissue changes. Eighty patients requiring one single crown or one fixed partial prosthesis supported by a maximum of three implants were randomised, after implants were placed with more than 35 Ncm, according to a parallel group design to receive definitive abutments which were loaded immediately (definitive abutment or immediate loading group) or transmucosal abutments. These were delayed loaded after 3 months and were removed at least three times: 1) at impression taking (3 months after implant placement); 2) when checking the zirconium core on titanium abutments at single crowns or the fitting the metal structure at prostheses supported by multiple implants; 3) at delivery of the definitive prostheses (repeated disconnection or conventional loading group). Patients were treated in four centres and each patient contributed to the study with only one prosthesis followed for 1 year after initial loading. Outcome measures were: prosthesis failures, implant failures, complications, pink esthetic score (PES), buccal recessions, patient satisfaction, peri-implant marginal bone level changes and height of the keratinised mucosa. Forty patients were randomly allocated to each group according to a parallel group design. Two patients dropped out from the definitive abutment group but no implant failed. Four provisional and one definitive single crowns had to be remade (due of misfitting) and one definitive crown (due to ceramic fracture) in the repeated disconnection group versus one provisional prosthesis of the immediate loading group due to frequent debondings (difference = 12%; CI95%: 0%, 25%; P = 0.109). Eight patients were affected by complications: four patients from each group (difference = 1%; CI95%: -13%, 14%; P = 1). PES scores assessed at 1 year post-loading were 11.4 (1.5) mm for the definitive abutment group and 11.0 (2.0) mm for the repeated abutment changes group (difference = 0.4; CI95%: -0.4, 1.2; P = 0.289). Buccal recessions at 1 year post-loading amounted to 0.07 (0.35) mm for the definitive abutment group and 0.12 (0.65) mm for the repeated abutment changes group (actually it was a soft tissue gain; difference = 0.05 CI 95%: -0.19, 0.29; P = 0.659). All patients declared to be very satisfied or satisfied with the function and aesthetics of the prostheses and would undergo the same procedure again. Mean peri-implant marginal bone loss at 1 year after loading was 0.06 (0.12) mm for the definitive abutment group and 0.23 (0.49) mm for the repeated abutment changes group (difference = -0.16; CI95%: -0.33,-0.00; P = 0.046). The height of the keratinised mucosa at 1 year post-loading was 2.8 (1.5) mm for the definitive abutment group and 2.8 (1.7) mm for the repeated abutment changes group (difference = -0.0; CI 95%: -0.8, 0.7); P = 0.966. Up to 1 year after initial loading, there were no statistically significant differences between the two procedures, with the exception of 0.16 mm more marginal bone loss at implants subjected to three abutment removals. One-year post-loading data showed that repeated abutment changes significantly increased bone loss of 0.16, but this difference cannot be considered clinically relevant, therefore clinicians can use the procedure they find more convenient for their specific patient. In addition, immediately non-occlusally loaded dental implants are a viable alternative to conventional loading. Conflict-of-interest statement: This trial was partially funded by Dentsply Sirona Implants, the manufacturer of the implants and other products evaluated in this investigation. However, data belonged to the authors and by no means did the manufacturer interfere with the conduct of the trial or the publication of the results with exception of rejecting the proposal of changing the protocol, after the trial was started, allowing the use of indexed abutments.


Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis.
The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis.


Assembly properties of bacterial actin MreB involved in Spiroplasma swimming motility.
Bacterial actin MreB forms filaments composed of antiparallel double-stranded units. The wall-less helical bacterium Spiroplasma has five MreB homologs (MreB1-5), some of which are involved in an intracellular ribbon for driving the bacterium's swimming motility. Although the interaction between MreB units is important for understanding Spiroplasma swimming, the interaction modes of each ribbon component are unclear. Here, we examined the assembly properties of Spiroplasma eriocheiris MreB5 (SpeMreB5), one of the ribbon component proteins that forms sheets. Electron microscopy revealed that sheet formation was inhibited under acidic conditions and bundle structures were formed under acidic and neutral conditions with low ionic strength. We also used solution assays and identified four properties of SpeMreB5 bundles as follows: (I) bundle formation followed sheet formation; (II) electrostatic interactions were required for bundle formation; (III) the positively charged and unstructured C-terminal region contributed to promoting lateral interactions for bundle formation; and (IV) bundle formation required Mg2+ at neutral pH but was inhibited by divalent cations under acidic pH conditions. During these studies, we also characterized two aggregation modes of SpeMreB5 with distinct responses to ATP. These properties will shed light on SpeMreB5 assembly dynamics at the molecular level.


Rotavirus (reovirus-like) infection of neonatal ruminants in a zoo nursery.
An outbreak of a pneumoenteric disease occurred in neonates in a zoo nursery. Four of seven affected animals died. Rotaviruses were observed in the feces of an affected 4-day old impala (Aepyceros melampus), a Thomson's gazelle (Gazella thomsonii) and an addax (Addax nasomaculatus). Encapsulated Escherichia coli also were isolated from the feces. The recovered rotaviruses was antigenically related to bovine rotavirus. A bovine rotavirus vaccine was given orally and no adverse effects were noted.


Caenorhabditis elegans deep lipidome profiling by using integrative mass spectrometry acquisitions reveals significantly altered lipid networks.
Lipidomics coverage improvement is essential for functional lipid and pathway construction. A powerful approach to discovering organism lipidome is to combine various data acquisitions, such as full scan mass spectrometry (full MS), data-dependent acquisition (DDA), and data-independent acquisition (DIA). Caenorhabditis elegans (C. elegans) is a useful model for discovering toxic-induced metabolism, high-throughput drug screening, and a variety of human disease pathways. To determine the lipidome of C. elegans and investigate lipid disruption from the molecular level to the system biology level, we used integrative data acquisition. The methyl-tert-butyl ether method was used to extract L4 stage C. elegans after exposure to triclosan (TCS), perfluorooctanoic acid, and nanopolystyrene (nPS). Full MS, DDA, and DIA integrations were performed to comprehensively profile the C. elegans lipidome by Q-Exactive Plus MS. All annotated lipids were then analyzed using lipid ontology and pathway analysis. We annotated up to 940 lipids from 20 lipid classes involved in various functions and pathways. The biological investigations revealed that when C. elegans were exposed to nPS, lipid droplets were disrupted, whereas plasma membrane-functionalized lipids were likely to be changed in the TCS treatment group. The nPS treatment caused a significant disruption in lipid storage. Triacylglycerol, glycerophospholipid, and ether class lipids were those primarily hindered by toxicants. Finally, toxicant exposure frequently involved numerous lipid-related pathways, including the phosphoinositide 3-kinase/protein kinase B pathway. In conclusion, an integrative data acquisition strategy was used to characterize the C. elegans lipidome, providing valuable biological insights into hypothesis generation and validation.


Identification of two novel rice S genes through combination of association and transcription analyses with gene-editing technology.
Traditional rice blast resistance breeding largely depends on utilizing typical resistance (R) genes. However, the lack of durable R genes has prompted rice breeders to find new resistance resources. Susceptibility (S) genes are potential new targets for resistance genetic engineering using genome-editing technologies, but identifying them is still challenging. Here, through the integration of genome-wide association study (GWAS) and transcriptional analysis, we identified two genes, RNG1 and RNG3, whose polymorphisms in 3'-untranslated regions (3'-UTR) affected their expression variations. These polymorphisms could serve as molecular markers to identify rice blast-resistant accessions. Editing the 3'-UTRs using CRISPR/Cas9 technology affected the expression levels of two genes, which were positively associated with rice blast susceptibility. Knocking out either RNG1 or RNG3 in rice enhanced the rice blast and bacterial blight resistance, without impacting critical agronomic traits. RNG1 and RNG3 have two major genotypes in diverse rice germplasms. The frequency of the resistance genotype of these two genes significantly increased from landrace rice to modern cultivars. The obvious selective sweep flanking RNG3 suggested it has been artificially selected in modern rice breeding. These results provide new targets for S gene identification and open avenues for developing novel rice blast-resistant materials.


Expression of orexin B and its receptor 2 in rat testis.
The peptides orexin A (OxA) and orexin B (OxB) deriving from a common precursor molecule, prepro-orexin, by proteolytic cleavage, bind the two G-coupled OX1 and OX2 receptors. While OX1 selectively binds OxA, OX2 shows similar affinity for both orexins. Firstly discovered in the hypothalamus, orexins and their receptors have been found in other brain regions as well as in peripheral tissues of mammals, thus resulting involved in the regulation of a broad variety of physiological functions. While the functional localization of OxA and OX1 in the mammalian genital tract has been already described, the expression of OxB and OX2 and their potential role in the reproductive functions remain to be explored. Here, we investigated the presence of OxB and OX2 in the rat testis by immunohistochemical and biochemical analyses. The results definitely demonstrated the localization of OxB and OX2 in pachytene and second spermatocytes as well as in spermatids at all stages of the cycle of the seminiferous epithelium. The expression of both OX2 mRNA and protein in the rat testis was also established by RT-PCR and Western blotting, respectively. The analysis of the molecular mechanism of action of OxB in the rat testis showed that OxB, in contrast with OxA, is unable to promote steroidogenesis. These results translate into the regulation of diverse biological actions by OxA and OxB in the male gonad.


Nanometer-scaled landscape of polymer: fullerene blends mapped with visibles-SNOM.
Bulk heterojunction is one key concept leading to breakthrough in organic photovoltaics. The active layer is expectantly formed of distinct morphologies that carry out their respective roles in photovoltaic performance. The morphology-performance relationship however remains stymied, because unequivocal morphology at the nanoscale is not available. We used scattering-type scanning near-field optical microscopy operating with a visible light source (visibles-SNOM) to disclose the nanomorphology of P3HT:PCBM and pBCN:PCBM blends. Donor and acceptor domain as well as intermixed phase were identified and their intertwined distributions were mapped. We proposed energy landscapes of the BHJ active layer to shed light on the roles played by these morphologies in charge separation, transport and recombination. This study shows that visibles-SNOM is capable of profiling the morphological backdrop pertaining to the operation of high performance organic solar cells.


Resilience from the perspective of diagnostic radiography students.
Resilience is a concept associated with the ability to overcome, adapt, and recover from stressors. The radiography profession is known to be stressful, and one can reason that radiographers must be resilient in order to cope with the clinical environment. Research shows there are varied understandings of resilience. However, little is known about the concept of resilience specifically as it relates to the perspectives of diagnostic radiography students within the clinical workplace. This paper reports on one aspect of a comprehensive study of resilience amongst radiography students. The objective of this paper is, therefore, to present the exploration of the concept of resilience drawing from the data gathered from first-year diagnostic radiography students. A qualitative, explorative, descriptive and contextual approach was adopted for this study. Qualitative data was collected through focus group interviews. A purposive sampling method was employed, selecting from first-year diagnostic radiography students at a University of Technology (UoT) in the Western Cape, South Africa. Interviews were audio-recorded transcribed and thematically analysed. Data was collected until saturation was reached. The meaning of resilience as explained from the perspective of radiography students included three subthemes namely: (1) fundamentals of resilience; (2) external protective factors and (3) internal protective factors. This study demonstrated that radiography students associated resilience with positive attributes. Furthermore, the study identified various resilience enhancement strategies to better support diagnostic radiography students in the clinical environment like supportive radiographers and talking to peers. The identification of resilience enhancement strategies is important as it will assist with the introduction of curriculum renewal initiatives tailored to support first-year diagnostic radiography students as they develop their resilience to stressors in the clinical environment.


Participants' perceptions of a mandated training course in the identification and reporting of child abuse.
Professionals (N = 844) from various disciplines who had participated in a mandated training course in identifying and reporting child abuse were surveyed regarding their perceptions of the experience. The majority of the 540 professionals who responded felt that learning objectives had been met, teaching methods were appropriate, the trainers were effective teachers, and the course content was relevant and applicable to their practice. Solicited comments and recommendations reflected trends in professionals' perceptions.


Early Impact on Renal Parenchymal Vascularization of Chimney Grafts Versus Fenestrated Grafts.
The primary objective of this retrospective study was to analyze the early impact of chimney (CG) versus fenestrated grafts (FG) on renal parenchymal vascularization and function. All consecutive patients with juxta-renal abdominal aortic aneurysm (JR-AAA) treated by endovascular repair from December 2013 to July 2014 at the vascular unit, Pellegrin University Hospital, Bordeaux, France, were included. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were reported at baseline and at J2 for acute kidney injury (AKI) incidence, and at J7 for AKI staging (KDIGO criteria); renal resistive indices (RRI) were reported for renal parenchymal repercussion at J-1, J0, and J1. Ten patients were included in the CG group and 25 in the FG group, with 13 and 50 renal target vessels, respectively. Successful target vessel revascularization was achieved in 92.3% and 100.0% of patients. The incidence of AKI (10% and 32%), baseline SCr, and eGFR did not differ significantly. SCr was more elevated in the FG group at J1 (p = .025), J2 (p = .051), and J7 (p = .052), and eGFR was significantly lower from baseline to J1 (p = .015) and J2 (p = .014). RRI did not differ significantly between both groups. RRI augmentation was only noted in the FG group from J-1 to J0 (p = .039) and J-1 to J1 (p = .059). Patients with a KDIGO score <2 versus ≥2 showed significantly different RRI at J0 (p = .038) and J1 (p = .007). ROC curve analysis showed that RRI measures could be a predictive factor for AKI at J0 (cutoff = 0.72, sensitivity [Se] = 50%, specificity [Sp] = 86%) and J1 (cutoff = 0.71, Se = 70%, Sp = 84%). This study showed no significant difference in terms of RRI, eGFR, and the incidence of AKI or CKD between CG and FG. However, post-operative SCr levels were higher with FG, which was corroborated by comparison between pre- and post-operative RRI. Results are limited by the small sample size, but early repeated measures of RRI could be helpful in alerting the clinician to post-operative renal degradation, allowing better-informed attempts to preserve renal function.


Structure-function similarities in deep brain stimulation targets cross-species.
Deep Brain Stimulation (DBS) is an effective neurosurgical treatment to alleviate motor symptoms of advanced Parkinson's disease. Due to its potential, DBS usage is rapidly expanding to target a large number of brain regions to treat a wide range of diseases and neuropsychiatric disorders. The identification and validation of new target regions heavily rely on the insights gained from rodent and primate models. Here we present a large-scale automatic meta-analysis in which the structure-function associations within and between species are compared for 21 DBS targets in humans. The results indicate that the structure-function association for the majority of the 21 included subcortical areas were conserved cross-species. A subset of structures showed overlapping functional association. This can potentially be attributed to shared brain networks and might explain why multiple brain areas are targeted for the same disease or neuropsychiatric disorder.


Effects of dopexamine in comparison with fenoterol on carbohydrate, fat and protein metabolism in healthy volunteers.
In critically ill patients adrenergic agonists are used to treat haemodynamic disorders. Their metabolic actions should be considered in controlling metabolic homeostasis. Dopexamine has assumed effects on carbohydrate, fat and protein metabolism. The aim of this study was to define its metabolic actions and compare these with those of fenoterol by using a stable isotope dilution technique. Prospective, randomized experimental study. Experimental section of a university anaesthesiology department. Twenty-seven healthy male volunteers in three groups with nine participants each. Participants received a 4-h infusion of dopexamine (2.25 microg/kg per min), fenoterol (at least 0.025 microg/kg per min) or saline. Before and every 80 min during drug infusion, we measured endogenous glucose production and the plasma appearance rates for leucine and urea. In addition, we measured plasma concentrations of glucose, lactate, free fatty acids (FFAs), noradrenaline, adrenaline, insulin, glucagon and potassium. Endogenous glucose production did not differ among the groups. Glucose plasma concentration and glucose clearance remained constant during the dopexamine infusion. Fenoterol increased glucose plasma concentration and decreased glucose clearance. Lactate, FFAs, insulin and noradrenaline plasma concentrations were increased and the rate of leucine appearance was decreased by both drugs. The rate of urea appearance did not differ from the control group. Dopexamine has no or only weak effects on carbohydrate metabolism, its effects on fat and protein metabolism are comparable to those of fenoterol. This metabolic profile may be advantageous in increasing cardiac output in patients with impaired glucose tolerance.


Nutritional deficiency dermatitis related to branched-chain amino acid restriction in a child with maple syrup urine disease.
We present a one-year-old girl with maple syrup urine disease with dermatitis secondary to the restriction of amino acids as part of the treatment. We present the clinical evolution and histopathological correlation.


Synthesis and characterization of V2 O5 /urease for a biosensor of urea.
Vanadium pentoxide (V2 O5 ) was used as support material to immobilize the urease enzyme. V2 O5 was prepared from a sol-gel process, and the immobilization of urease was done onto the surface of the PET/ITO/V2 O5 film. Different concentrations of urea were tested to study the sensitivity of the biosensor. Tests with pH variation were carried out, and it was noticed that the total charge in the cyclic voltammograms decreases due to the increase in pH that influences the catalytic activity of the enzyme. From cyclic voltammograms, with a different scan rate, for linear correlation testing, it was observed that the anodic currents varied as a function of the scan rate. Based on the variation in the urea concentration, the current increased with the increase in the urea concentration, indicating the sensitivity of the material. The use of V2 O5 /urease showed favorable electrochemical responses for application in biosensors as well as being sensitive to the variation in the urea concentration and easy to obtain and prepare.


M- and L-cones in early infancy: III. Comparison of genotypic and phenotypic markers of color vision in infants and adults.
Genetic analyses were performed on five male children (approximately 3 years), two suspect color-normals and three suspects for congenital color vision deficiencies. These classifications were based on visually-evoked potential (VEP) responses to M- and L-cone-isolating stimuli obtained in a previous study when each subject was either 4- or 8-weeks old. The present analyses were performed in a blind study to characterize the genotypes of these subjects. Four male adults with various color vision phenotypes were also tested as a control. DNA was isolated using a non-invasive technique followed by polymerase chain reaction (PCR) amplification and restriction enzyme analysis to examine the genomic DNA of each subject. The genetic analyses confirmed the VEP identification of two color defective infants, and were consistent with the diagnosis of two other infants as color normal. A third infant was predicted by VEP analysis to have a protan defect, but he did not have a gene array typically found in protan observers.


Composition and antimicrobial activity of essential oils from Centaurea sessilis and Centaurea armena.
The essential oils of air-dried Centaurea sessilis and Centaurea armena obtained by hydrodistillation were analyzed by gas chromatography-mass spectrometry (GC-MS). Forty and twenty components were identified in the essential oils and the main component of these taxons was beta-eudesmol in the ratios of 12.4% and 19.3% from C. sessilis and C. armena, respectively. The antimicrobial activity of the isolated essential oil of the plants was also investigated. They showed moderate antibacterial activity against Gram-positive and Gram-negative bacteria, but no antifungal activity was observed against two yeastlike fungi.


Fuel-mediated teratogenesis: symmetric growth retardation in the rat fetus at term after a circumscribed exposure to D-mannose during organogenesis.
We previously infused the D-glucose epimer D-mannose into pregnant rats to deliver a brief metabolic insult to the early postimplantation conceptus. This insult caused developmental anomalies and growth retardation that were apparent in the embryos 2 days later. We now report the long-range effects on intrauterine development of such a circumscribed metabolic insult during organogenesis. Ten pregnant animals were infused with D-mannose for 12 hours during early neurulation (day 9.5 to 10 of development). Ten control animals were infused with equimolar D-glucose during this same time interval. Mannose infusions produced maternal plasma mananose concentrations in the embryotoxic range; glucose infusions caused only slight and transient hyperglycemia. Fetuses were removed at term and examined for evidence of developmental anomalies and growth retardation. None of 137 fetuses from the mannose group or 138 fetuses from the glucose group exhibited gross anomalies. However, an excess of resorbed conceptions in the mannose group (21 versus six in the glucose group; p less than 0.01) suggested some lethal toxicity from mannose exposure during embryogenesis. Among viable fetuses, the mean body weight of those from the mannose group was significantly reduced compared with those from the glucose group (5.62 +/- 0.04 versus 5.89 +/- 0.03 gm, respectively; p less than 0.001). Reductions of a similar magnitude were noted in the mean wet weight and protein content of fetal brains, hearts, livers, and kidneys from the mannose group (range, 3.4% to 7.1% below the glucose group), indicating a symmetric pattern of fetal growth retardation. In addition, analysis of fetal ossification sites after Alizarin Red S staining revealed a significant delay of skeletal development in the mannose group. These results indicate that a relatively brief metabolic insult to embryos during early organogenesis may cause lethal developmental anomalies as well as growth retardation and delayed skeletal development that are manifested in the fetus at term.


Awareness of inner experience: a systems perspective on self-regulatory process in early development.
This brief synopsis of an organizational perspective on early development represents an integration of three major areas of the author's research: that of a detailed observational study of early mother-infant interaction over the first three years of life; that of a continuous neonatal state and caregiving interactional monitoring method over the first two months of life; and that of a 25- to 30-year follow-up on the same infants observed initially. From these data a ground plan is proposed for our thinking about the individual's life span trajectory as a unique construction within a unique context for that individual's interactional and adaptive self-regulatory strategies. Beginning with a review of biological principles, the paradoxical integration of complexity and unity in living systems is traced from the conceptualization of infant state and observations on its regulation through the role of state in the origins of awareness of inner experience, to the consolidation and validation of the self as agent in self-regulation. Central to integration is the recognition process, stemming from one's awareness that another is aware of what one is aware of within oneself. The constructionist perspective on the critical role of specificity in this organizing process is illustrated by reference to the negotiation between caregiver and infant of seven issues of adaptive coordination over the first three years of life. Finally, five propositions are formulated describing such specificity in this organizing process, as one that underlies integration of levels of the living system relating the biological, the developmental, the shaping of the life span trajectory, and the reconstructive therapeutic process.


Aortic isthmus Doppler in normal and small-for-gestational-age fetuses and its association with prediction of adverse perinatal outcome.
To establish reference ranges for aortic isthmus Doppler indices in appropriate-for-gestational-age (AGA) fetusesand to evaluate its association with perinatal outcome in small-for-gestational-age (SGA) fetuses. Prospective cohort observational study in which 30 pregnant women with SGA fetuses and 60 women with AGA fetuses were recruited from the prenatal clinic of the hospital. The AGA group was eventually followed from 24 weeks by 4-weekly Doppler assessment, and the SGA group was examined as per institutional protocol. We analyzed the data using STATA version 14.0 statistical software. Continuous variables were examined for normality assumption using the Kolmogorov-Smirnov test. To develop a nomogram for appropriate gestational age, we adopted a mixed linear model analysis. For each of the variables Ao pulsatility index (PI), Ao peak systolic velocity (PSV), Ao systolic nadir (Ns), and Ao isthmic systolic index (ISI) mean predicted values, 3rd centile and 97th centile were calculated based on the parameter estimation of mixed model. Observed data for each of the variables in the SGA group were plotted in the nomogram developed for the AGA group to show the trend of SGA data in comparison to AGA data. The total number of observations made on 60 AGA and 30 SGA fetuses were 240 and 67, respectively. Nomograms for the 3rd and 97th centiles were derived for Ao PI, Ao PSV, Ao Ns, and Ao ISI. Mean Ao PI values were significantly higher in SGA group (2.37 vs 2.22; P < .05); mean Ao PSV was significantly lower in the SGA group (67.1 vs 76.3; P < .05), but mean Ao Ns and mean Ao ISI values were significantly higher in the SGA group (-5.24 vs 2.0 and -0.04 vs -0.01; P < .05). Aortic Doppler assessment seems to provide beneficial information for monitoring small fetuses. Ao PI and Ao ISI, which were raised in fetuses with SGA, can be used in prognosis.


Predictive factors for obstetric anal sphincter injury in primiparous women: systematic review and meta-analysis.
The primary objective was to perform a systematic review of predictive factors for obstetric anal sphincter injury (OASI) occurrence at first vaginal delivery, with the diagnosis made by ultrasound (US-OASI). The secondary objective was to report on incidence rates of sonographic anal sphincter (AS) trauma, including trauma that was not clinically reported at childbirth, among the studies providing data for our primary objective. We conducted a systematic search of MEDLINE, EMBASE, Web of Science, CINAHL, The Cochrane Library and ClinicalTrials.gov databases. Both observational cohort studies and interventional trials were eligible for inclusion. Study eligibility was assessed independently by two authors. Random-effects meta-analyses were performed to pool effect estimates from studies reporting on similar predictive factors. Summary odds ratio (OR) or mean difference (MD) is reported with 95% CI. Heterogeneity was assessed using the I2 statistic. Methodological quality was assessed using the Quality in Prognosis Studies tool. A total of 2805 records were screened and 21 met the inclusion criteria (16 prospective cohort studies, three retrospective cohort studies and two interventional non-randomized trials). Increasing gestational age at delivery (MD, 0.34 (95% CI, 0.04-0.64) weeks), shorter antepartum perineal body length (MD, -0.60 (95% CI, -1.09 to -0.11) cm), labor augmentation (OR, 1.81 (95% CI, 1.21-2.71)), instrumental delivery (OR, 2.13 (95% CI, 1.13-4.01)), in particular forceps extraction (OR, 3.56 (95% CI, 1.31-9.67)), shoulder dystocia (OR, 12.07 (95% CI, 1.06-137.60)), episiotomy use (OR, 1.85 (95% CI, 1.11-3.06)) and shorter episiotomy length (MD, -0.40 (95% CI, -0.75 to -0.05) cm) were associated with US-OASI. When pooling incidence rates, 26% (95% CI, 20-32%) of women who had a first vaginal delivery had US-OASI (20 studies; I2 = 88%). In studies reporting on both clinical and US-OASI rates, 20% (95% CI, 14-28%) of women had AS trauma on ultrasound that was not reported clinically at childbirth (16 studies; I2 = 90%). No differences were found in maternal age, body mass index, weight, subpubic arch angle, induction of labor, epidural analgesia, episiotomy angle, duration of first/second/active-second stages of labor, vacuum extraction, neonatal birth weight or head circumference between cases with and those without US-OASI. Antenatal perineal massage and use of an intrapartum pelvic floor muscle dilator did not affect the odds of US-OASI. Most (81%) studies were judged to be at high risk of bias in at least one domain and only four (19%) studies had an overall low risk of bias. Given the ultrasound evidence of structural damage to the AS in 26% of women following a first vaginal delivery, clinicians should have a low threshold of suspicion for the condition. This systematic review identified several predictive factors for this. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.


No adverse effect of outdoor air pollution on HbA1c in children and young adults with type 1 diabetes.
Evidence is growing that air pollutants deteriorate glucose metabolism and insulin sensitivity by oxidative stress and inflammation. This might affect HbA1c levels and insulin requirements in type 1 diabetes. There are no data available on this association. Air pollution values of respirable particulate matter (PM10), nitrogen dioxides (NO2), and accumulated ozone (O3-AOT40) were obtained from the federal environmental agency (Umweltbundesamt II) and assigned to place of residence of 840 participants from a nation-wide population-based type 1 diabetes registry (German Diabetes Center, Düsseldorf, Germany). Information on HbA1c, social status, treatment and co-morbidities was collected by self-administered questionnaires. Complete information was available for 771 patients aged 11-21 years at the time of study. In linear regression models, no adverse effects of air pollutants (PM10, NO2 or O3-AOT40 on HbA1c level were found, but O3-AOT40 was inversely associated with HbA1c (mmol/mol) in the crude (estimate per IQR: -1.86; 95% CI: (-3.27; -0.44); p=0.01) and the best model adjusting for lifestyle, socioeconomic factors, clinical information, and season (-1.50; (-2.82; -0.17); 0.034). After adding area of residency as random effect to the crude and the best model, the association was no longer significant (-1.64; (-3.84; 0.56); 0.14); (-1.56; (-3.67; 0.55); 0.14). Adjustment for further possible confounders did not affect the estimates seriously. None of the pollutants was associated with insulin dose (IU/kg body weight). Investigated pollutants had no adverse effect on metabolic control in children and young adults with type 1 diabetes in this cross-sectional study. The weak inverse association of accumulated ozone with HbA1c might be due to confounding by regional characteristics or regional aspects of care.


Early membrane lipid changes in laminectomized and traumatized cat spinal cord.
The effects of surgical exposure (laminectomy) and compression trauma on various aspects of membrane lipid metabolism in the feline spinal cord were determined in this study. Tissue samples were frozen in situ and grossly dissected into gray and white portions prior to lipid analyses. Laminectomy alone resulted in measurable changes in spinal cord lipid metabolism, including increases in gray matter free fatty acids, diacylglycerols, and eicosanoids. A 90-min recovery period greatly reduced the levels of these compounds. Compression of the spinal cord with a 170-g weight (following a 90-min recovery period) caused very large increases in gray matter free fatty acids, diacylglycerols, and eicosanoids, and decreases in cholesterol and ethanolamine plasmalogens. Similar, but time delayed changes in these compounds were also observed in white matter.


Machine Learning Applied to the Modeling of Pharmacological and ADMET Endpoints.
The well-known concept of quantitative structure-activity relationships (QSAR) has been gaining significant interest in the recent years. Data, descriptors, and algorithms are the main pillars to build useful models that support more efficient drug discovery processes with in silico methods. Significant advances in all three areas are the reason for the regained interest in these models. In this book chapter we review various machine learning (ML) approaches that make use of measured in vitro/in vivo data of many compounds. We put these in context with other digital drug discovery methods and present some application examples.


Clinical effect of T-SPOT.TB test for the diagnosis of tuberculosis.
The goal of this study was to further investigate the clinical effectiveness of the T-SPOT.TB test in diagnosing tuberculosis (TB), including the effects of T-SPOT.TB test on evaluating diverse TB types and locations. We collected 20,332 specimens from patients suspected to have TB. Afterwards, we performed an integrative analysis of T-SPOT.TB results and clinical diagnoses, and evaluated the composition ratio and positive detection rate of the T-SPOT.TB test in various age groups, sample types, and hospital departments. In addition, we compared the spot number and composition rate between latent TB infection (LTBI), active TB infection, and old TB infection groups. The active TB group was then further divided into pulmonary TB (PTB), pulmonary and extrapulmonary TB (PETB), and extrapulmonary TB (EPTB) subgroups, and we evaluated whether there were statistical differences in spot number and composition rate between subgroups. Positive results from the T-SPOT.TB test were found across different age groups, specimen types, and hospital departments. Elderly patient groups, pleural effusion samples, and thoracic surgery departments showed the highest rates of positivity. There were no statistically significant differences in spot number of CFP-10 and ESAT-6 wells between disease groups or active TB subgroups. The composition rate, however, was significantly different when ESAT-6 and CFP-10 wells were double-positive. The spot number and composition rate were statistically different between the three disease groups, but showed no significant differences between the three subgroups of active TB. The results of T-SPOT. TB test showed differences in LTBI, active TB and old TB. Additionally, a higher spot number level was observed in the active TB group.


Prognostic model of 10 immune-related genes and identification of small molecule drugs in bladder urothelial carcinoma (BLCA).
We aimed to establish an immune-related gene (IRG) based signature that could provide guidance for clinical bladder cancer (BC) prognostic surveillance. Differentially expressed IRGs and transcription factors (TFs) between BCs and normal tissues were extracted from transcriptome data downloaded from the TCGA database. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to identify related pathways based on differently expressed IRGs. Then, univariate Cox regression analysis was performed to investigate IRGs with prognostic values and LASSO penalized Cox regression analysis was utilized to develop the prognostic index (PI) model. A total of 411 BC tissue samples and 19 normal bladder tissues in the TCGA database were enrolled in this study and 259 differentially expressed IRGs were identified. Networks between TFs and IRGs were also provided to seek the upstream regulators of differentially expressed IRGs. By means of univariate Cox regression analysis, 57 IRGs were analyzed with prognostic values and 10 IRGs were finally identified by LASSO penalized Cox regression analysis to construct the PI model. This model could significantly classified BC patients into high-risk group and low-risk group in terms of OS (P=9.923e-07) and its AUC reached 0.711. By means of univariate and multivariate COX regression analysis, this PI was proven to be a valuable independent prognostic factor (HR =1.119, 95% CI =1.066-1.175, P<0.001). CMap database analysis was also utilized to screen out 10 small molecules drugs with the potential for the treatment of BC. Our study successfully provided a novel PI based on IRGs with the potential to predict the prognosis of BC and screened out 10 small molecules drugs with the potential to treat BC. Besides, networks between TFs and IRGs were also displayed to seek its upstream regulators for future researches.


Multi-Resolution FOCUSS: a source imaging technique applied to MEG data.
A variety of techniques are available for imaging magnetoencephalographic (MEG) data to the corresponding cortical structures. Each performs a functional optimization that includes mathematical and physical restrictions on source activity. Unlike other imaging techniques, MR-FOCUSS (Multi-Resolution FOCal Underdetermined System Solution) utilizes a wavelet statistical operator that allows spatial resolution to be chosen appropriately for focal or extended sources. Control of focal imaging properties is achieved by specifying P in an l(P) norm distribution template used to construct the wavelets. In addition, incorporation of a multi-resolution wavelet operator desensitizes the mathematical algorithm to noise, (regularization). Like the FOCUSS imaging technique, an initial estimate of cortical activity is recursively enhanced to obtain the final high resolution imaging results. Studies of model MEG data representing all regions of a realistic cortical model are performed to quantify MR-FOCUSS imaging properties. These modeled data studies included single and multiple dipole sources as well as an extended source model. Thus, MR-FOCUSS is found to be very effective for imaging language processing for pre-surgical planning and provides a high-resolution method to image sequential activation of multiple correlated sources involved in language processing.


Effect of cannabichromene on hepatic microsomal enzyme activity in the mouse.
1. Pretreatment with a Cannabis constituent, cannabichromene (CBC), i.p., had no effect on in vitro hepatic microsomal enzyme activity compared to a known inhibitor of these systems, SKF 525-A. 2. The results indicate that the previously reported CBC potentiation of CNS depressant-induced hypnosis is not mediated by the hepatic microsomal enzyme system.


Agency in the process of change: Investigating the experience of patients with obsessive-compulsive disorder and their counsellors.
The aim of this study was to explore how client's agency appears in the narratives of patients with obsessive compulsive disorder. A qualitative descriptive design was used as a study design and a thematic analysis was employed to collect and analyse the data. Semi-structured interviews were conducted with 37 participants (26 patients with obsessive compulsive disorder and 11 counselors). All patients had received tele-counseling. Three main themes were extracted from the data including agency prior to the therapy, agency via awareness, and enhancers of client's agency. Findings demonstrated that when the participants became aware of having OCD and underwent therapy with self-involvement, they achieved a higher level of agency in the therapy process and achieve better treatment results. Culture may also influence on how the disorder is experienced, and the level of agency in starting and following the required treatments. The results could be used by counsellors to enhance their clients' agency.


Role of COOH-terminal phosphorylation in the regulation of casein kinase I delta.
Casein kinase I delta is a member of the casein kinase I (CKI) family, a group of second messenger independent protein kinases. We present evidence that the COOH-terminal domain of CKI delta has regulatory properties. CKI delta expressed in Escherichia coli was activated by heparin, as found previously, and by treatment with the catalytic subunit of type-1 protein phosphatase (CS1). Concomitant with activation by CS1, there was a reduction in the apparent molecular weight of CKI delta from 55,000 to 49,000 as judged by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Truncation of CKI delta by removal of the COOH-terminal 110 amino acids eliminated the ability of CS1 to activate or to increase electrophoretic mobility. Casein kinase I alpha, a 37-kDa isoform that lacks an extended COOH-terminal domain, was not activated by CS1 or the presence of heparin. However, a chimeric enzyme consisting of CKI alpha fused to the COOH-terminal domain of CKI delta was activated by both heparin and CS1. Analysis of the effects of CS1 on a series of CKI delta COOH-terminal truncation mutants identified an inhibitory region between His317 and Pro342, which contained six potential phosphorylation sites. From analysis of the specific activites of these truncation mutants, removal of the same region resulted in enzyme with a specific activity nearly 10-fold greater than wild-type. Thus, CKI delta activity can be regulated by phosphorylation of its COOH terminus, which may serve to create an autoinhibitory domain. This mechanism of regulation could have important consequences in vivo.