Clinical, Immunophenotypic and Cytogenetic Features of Megakaryocytic Blast Crisis of Chronic Myeloid Leukemia: A Single Institution Study.
We present 15 patients with megakaryocytic (Mk) blast crisis (BC) of a Philadelphia (Ph) chromosome positive CML confirmed by immunophenotype analysis between 1989-2000. The primary aim of this study is to define clinical, immunological, cytogenetic and laboratory characteristics of Mk BC in Ph positive CML. We have done retrospective analysis regarding basic clinical findings, immunologic phenotype, cytogenetic studies and platelet functions. All patients had significant expression of CD61 (14/14) and CD34 (13/13) antigens, and a high frequency of expression of CD13 (9/12), CD33 (10/12) and CD11b (9/11). The BC in 6/15 patients was presented with thrombocytosis, 7/15 had a normal platelet count and two patients had thrombocytopenia. A grade IV myelofibrosis was present in 8/10 patients. Six patients evolved additional karyotypic abnormalities. Two patients had extramedullary BC. The serum activity of LDH (med. 1095.6) was elevated in all patients. A platelet dysfunction was documented in 4/5 patient tested. There are no clinical and hematological characteristics specific for Mk BC of CML. Normal or elevated platelet count (med. 427.4 x 109/L) in BC of CML with prominent expression of CD34 and CD61 antigens, and significant myelofibrosis (grade IV) are the most consistent clinical findings.


In vitro angiogenic activity of RNA from leukemic lymphocytes.
RNA was extracted from leukemic lymphocytes by a fluorocarbon method, and primary cultures of human amniotic cells were exposed to the lymphocyte RNA. Angioid tubular and cordon-like structures in branching out and criss-cross patterns with budding ends developed in these cultures within 7 to 12 days of the first exposure. Although there was no opportunity to study preparations from nonleukemic lymphocytes, extracts of normal peripheral blood cells and blood rich in granulocytes had no angiogenic effects. In view of the recent renewal of interest in tumor and tissue angiogenic factor as well as in angiogenic activity by transformed lymphocytes, in addition to the intriguing angioblastic component of Lukes-Rappaport immunoproliferative syndromes, this work may point to the ribonucleic acid nature of the vessel-forming principle. Various cell-differentiating properties of RNA preparations have been repeatedly described, and thus it is not altogether surprising that lymphocyte angiogenic factor may originate in RNA.


A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models.
Frequent infusions of intravenous factor VIII (FVIII) are required to prevent bleeding associated with hemophilia A. To reduce the treatment burden, recombinant FVIII with a longer half-life was developed without changing the protein structure. FVIII-polyethylene glycol (PEG) conjugates were prepared using an enzymatic process coupling PEG (ranging from 10 to 80 kDa) selectively to a unique O-linked glycan in the FVIII B-domain. Binding to von Willebrand factor (VWF) was maintained for all conjugates. Upon cleavage by thrombin, the B-domain and the associated PEG were released, generating activated FVIII (FVIIIa) with the same primary structure and specific activity as native FVIIIa. In both FVIII- and VWF-deficient mice, the half-life was found to increase with the size of PEG. In vivo potency and efficacy of FVIII conjugated with a 40-kDa PEG (N8-GP) and unmodified FVIII were not different. N8-GP had a longer duration of effect in FVIII-deficient mouse models, approximately a twofold prolonged half-life in mice, rabbits, and cynomolgus monkeys; however, the prolongation was less pronounced in rats. Binding capacity of N8-GP on human monocyte-derived dendritic cells was reduced compared with unmodified FVIII, resulting in several-fold reduced cellular uptake. In conclusion, N8-GP has the potential to offer efficacious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency.


Measuring population health using personal health messages.
Personal health messages - inter patient communications within online communities; represent a new path towards providing continuous information about patient derived health status. We apply natural language processing techniques to personal health messages from online message boards to demonstrate the ability to track trends in people's positive or negative opinion (sentiment) regarding particular drugs over time. The significant changes in sentiment correspond to FDA announcements and other publicity. We envision such analysis as a scalable tool for pharmacovigilance hypothesis generation for possible adverse drug reactions.


[Human placenta hydrolysates: from V.P. Filatov to the present day: Review].
Works of V.P. Filatov and his school laid the foundation for the study and clinical use of human placenta hydrolysates (HPH). To date, the PubMed database contains more than 5,000 publications on basic and clinical research on HPH. Studies of the peptide composition of HPH, carried out using the methods of modern proteomics, have made it possible to propose a complex of molecular mechanisms of the action of HPH in various pathologies. The article discusses the effects of HPH on the treatment of liver diseases, atopic dermatitis, viral infections (herpes, COVID-19, viral hepatitis), iron overload and chronic fatigue syndrome. Stimulation of HPH regenerative capabilities of the body is important for accelerating and improving the quality of wound healing, treatment of diseases of the joints and the reproductive system.


A case report of crusted scabies in an adult patient with Down syndrome.
Crusted (Norwegian) scabies is a severe manifestation of the contagious skin infection caused by Sarcoptes scabiei. Crusted scabies has been well described in patients with known immunocompromised states. Treatment may be complicated by delayed diagnosis and/or inadequate treatment. This infection may not rank highly on one's differential diagnosis in the absence of an immunocompromised state, highlighting the uniqueness of the case being presented. Several papers describe immunocompromised children with Down syndrome who are infected with crusted scabies. We present a case of infection in an adult with Down syndrome without evidence of an immunocompromised state. Our patient came to us with a 13-month history of progressively worsening symptoms, the last 4-6 weeks of that time period being most dramatic, despite various treatments. We performed tissue biopsy, culture, and laboratory evaluations, which revealed numerous mites and bacterial superinfection. Crusted scabies infection may occur in adult age individuals with Down syndrome regardless of immune status, leading us to encourage practitioners to consider this condition when presented with patients of this population. We also highlight the need for further exploration of disease prevalence in this patient population.


Risk factors associated with intestinal permeability in an adult population: A systematic review.
Increased intestinal permeability (IP) involves the loss of integrity between the cells of the small intestine. IP has been suggested to contribute to the pathogenesis and exacerbation of many chronic diseases. Many potential risk factors for IP are proposed in contemporary literature. The purpose of this review is to identify the most significant risk factors for IP. A systematic search of literature published up until September 2018 in the PubMed, EMBASE, CINAHL, and Scopus databases was conducted. A total of 47 articles met the inclusion criteria. Elevated levels of proinflammatory markers, dyslipidaemia, hyperglycaemia, insulin resistance, anthropometric measurements resembling obesity, advanced disease severity, comorbidity and the consumption of a Western-style diet were identified as the strongest risk factors for altered intestinal integrity. The risk of IP increases when coupled with a multiple disease state or combined with other environmental risk factors. Furthermore, many of the identified risk factors such as anthropometric measurements and biomarkers were external from intestinal health and rather resembled a metabolic-like condition. This review identified a number of potential risk factors for IP, ranging from biomarkers to anthropometric measurements, demographics, dietary intake and chronic diseases. These risk factors warrant the attention of clinicians and other healthcare providers to aid the identification of potential patients at risk of altered IP. Further research needs to examine whether the identified risk factors are homogeneous with the diagnosis of IP or whether the disease state influences the association.


Desmin: molecular interactions and putative functions of the muscle intermediate filament protein.
Desmin is the intermediate filament (IF) protein occurring exclusively in muscle and endothelial cells. There are other IF proteins in muscle such as nestin, peripherin, and vimentin, besides the ubiquitous lamins, but they are not unique to muscle. Desmin was purified in 1977, the desmin gene was characterized in 1989, and knock-out animals were generated in 1996. Several isoforms have been described. Desmin IFs are present throughout smooth, cardiac and skeletal muscle cells, but can be more concentrated in some particular structures, such as dense bodies, around the nuclei, around the Z-line or in costameres. Desmin is up-regulated in muscle-derived cellular adaptations, including conductive fibers in the heart, electric organs, some myopathies, and experimental treatments with drugs that induce muscle degeneration, like phorbol esters. Many molecules have been reported to associate with desmin, such as other IF proteins (including members of the membrane dystroglycan complex), nebulin, the actin and tubulin binding protein plectin, the molecular motor dynein, the gene regulatory protein MyoD, DNA, the chaperone alphaB-crystallin, and proteases such as calpain and caspase. Desmin has an important medical role, since it is used as a marker of tumors' origin. More recently, several myopathies have been described, with accumulation of desmin deposits. Yet, after almost 30 years since its identification, the function of desmin is still unclear. Suggested functions include myofibrillogenesis, mechanical support for the muscle, mitochondrial localization, gene expression regulation, and intracellular signaling. This review focuses on the biochemical interactions of desmin, with a discussion of its putative functions.


Quantification of Ephedrine Substances in Human Urine by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.
An accurate quantitative method for four prohibited ephedrine substances in human urine has been established, based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The quantitative bias caused by pretreatment operations and matrix effects was reduced by the dilute and shoot pretreatment method. The good separation of isomers was achieved with the advantages of the UPLC instrument and Agilent Poroshell 120 EC-C8 UPLC column. Stable quantitative ions were selected during the analysis with MS/MS. The result of the method validation experiment showed an excellent linearity between 50% and 200% threshold concentration with a correlation coefficient (r2) greater than 0.999. The coefficient of variation at the limit of quantification and threshold was <20% and 10%, respectively. The uncertainty was below the maximum uncertainty specified in the technical document of the World Anti-Doping Agency (WADA). The analytical result using this method has passed the WADA-external quality assessment scheme. The anti-doping laboratory has applied the method in routine tests and reported adverse analytical finding.


Reproducibility of jaw movements in patients with craniomandibular disorders.
It has never been investigated, if mandibular movements of patients with craniomandibular disorders (CMD) result in a lower reproducibility of dynamic functional parameters which are used for the individual articulator setting. The aim of the present study was to compare the reproducibility of electronically registered functional parameters in patients with CMD and in a control group. Dynamic functional parameters were recorded in 30 patients and 30 volunteers with a computerized ultrasound system (ARCUSdigma). The whole registration was performed three times during one session and three times at a second session 1 week later. The horizontal condylar inclination in the patient group gave a standard deviation of 2.17 degrees +/- 0.95 degrees , indicating poorer reproducibility than in the volunteer group, for which the standard deviation was 1.37 degrees +/- 0.42 degrees . The reproducibility of measurements of the Bennett angle was also poorer in the patient group than in the volunteer group, with standard deviations of 1.70 degrees +/- 0.62 degrees and 1.22 degrees +/- 0.40 degrees , respectively. The standard deviations calculated for determination of incisal inclination during laterotrusion was 3.02 degrees +/- 1.49 degrees for patients and 2.30 degrees +/- 1.17 degrees for volunteers. The standard deviations for incisal inclination during protrusion was 2.02 degrees +/- 0.95 degrees for patients and 2.06 degrees +/- 1.82 degrees for volunteers. The reproducibility of measurement of horizontal condylar inclination, Bennett angle and incisal inclination during laterotrusion therefore showed significantly lower reproducibility in the patient group than in the volunteer group (P < 0.05). The overall reproducibility of the measurements was nevertheless good in both groups, with standard deviations under 3.1 degrees , so that an individual setting of an articulator seems useful even in patients with CMD.


Crystal structures of the flavonoid Oroxylin A and the regioisomers Negletein and Wogonin.
The flavonoid Oroxylin A (6-methoxychrysin or 5,7-dihydroxy-6-methoxy-2-phenyl-4H-chromen-4-one, C16H12O5) and its regioisomers are of increasing interest for a variety of bioactive functions and their pharmaceutical formulation is of importance. Previous difficulties in the separation and misidentification of Oroxylin A from its regioisomers Wogonin (8-methoxychrysin or 5,7-dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one) and Negletein (5,6-dihydroxy-7-methoxyflavone or 5,6-dihydroxy-7-methoxy-2-phenyl-4H-chromen-4-one) render its full structural and powder X-ray characterization highly desirable. The low-temperature (100 K) crystal structures of Oroxylin A, Negletein and Wogonin sesquihydrate are reported for the first time. Wogonin crystallizes in two related but distinct hydrated forms. These have very similar powder diffractograms, indicating that such issues need to be addressed for its pharmaceutical formulation.


Upregulation of heat shock protein 70 and the differential protein expression induced by tumor necrosis factor-alpha enhances migration and inhibits apoptosis of hepatocellular carcinoma cell HepG2.
Tumor necrosis factor alpha (TNFα) plays diverse roles in liver damage and hepatocarcinogenesis with its multipotent bioactivity. However, the influence of TNFα on protein expression of hepatocellular carcinoma (HCC) is incompletely understood. Therefore, we aimed to investigate the differential protein expression of HCC in response to TNFα stimulus. We observed that HepG2 cell revealed a higher resistance to TNFα-induced apoptosis as compared to the non-tumorigenic hepatocyte THLE-2. By using a label-free quantitative proteomic analysis, we found that 520 proteins were differentially expressed in the HepG2 cells exposed to TNFα, including 211 up-regulated and 309 down-regulated proteins. We further confirmed several proteins with significant expression change (TNFα/control ratio>2.0 or <0.5) by immunoblotting using specific antibodies. We also analyzed the differential expressed proteins using Gene ontology and KEGG annotations, and the results implicated that TNFα might regulate ribosome, spliceosome, antigen processing and presentation, and energy metabolism in HepG2 cells. Moreover, we demonstrated that upregulation of heat shock protein 70 (HSP70) was involved in both the promoted migration and the inhibited apoptosis of HepG2 cells in response to TNFα. Collectively, these findings indicate that TNFα alters protein expression such as HSP70, which triggering specific molecular processes and signaling cascades that promote migration and inhibit apoptosis of HepG2 cells.


Cloning and characterization of a non-TIR-NBS-LRR type disease resistance gene analogue from peach.
Cloning of plant disease resistant genes is greatly helpful for disease resistant breeding in plants and the insight of resistance mechanism. However, there are less relevant researches in peach [prunus persica (L.) Batch]. In this study, four NBS-LRR type resistance gene analogs (RGAs) were cloned from genomic DNA of peach. The PNBS2 fragment was also amplified from peach cDNA and the full-length cDNA of PNBS2 (PRPM1, GenBank accession no. AY599223) has been cloned. Sequence analysis indicated that the cDNA of PRPM1 is 3007 bp in length and that the contained ORF encodes for a polypeptide of 917 amino acids. Compared with known NBS-LRR genes, it presented relatively high amino acid sequence identity. The polypeptide has typical structure of non-TIR-NBS-LRR genes, with NB-ARC, LZ, LRR and transmembrane domains. Southern analysis indicated that the PRPM1 gene might be a single copy in peach genome. Northern blot and RT-PCR analysis showed that the expression of PRPM1 was not induced by salicylic acid (SA) in peach young leaves. The isolation of putative resistance genes from peach provided useful bases for studying the structure and function of peach disease-resistance relating genes and disease resistant genetic breeding in peach.


Relationship of the erythrocyte sedimentation rate to acute phase proteins in polymyalgia rheumatica and giant cell arteritis.
We have compared the erythrocyte sedimentation rate (ESR) with other acute phase proteins (C-reactive protein (CRP), alpha(1) antitrypsin, orosomucoid, and haptoglobin) in 108 patients with polymyalgia rheumatica and/or giant cell arteritis. There was good correlation between CRP and ESR, but the ESR was also found to have the highest correlation with disease activity. The additional measurement of CRP or other acute phase proteins may be of value in a minority of cases.


Research on the influence of driving gas types in compound jet on extinguishing the pool fire.
Compound jet fire extinguishing technology is an efficient technology for oil fires. The hydrophobic ultrafine dry powder is used for the solid phase in the compound jet, but it can't be supplied continuously due to the insufficient supply of compressed nitrogen. Thus, the feasibility of using the compressed air to replace the compressed nitrogen in the compound jet was explored. The key factor for the replacement, which influences the fire extinguishing efficiency, is the oxygen content in the contact point between the jet and the flame. Firstly, the oxygen content of the ultrafine powder jet driven by air or nitrogen were investigated by gas analyzer; Secondly, 150 L (liter) gas oil and 50 L water were put in a oil pan, the compared fire extinguishing experiments were conducted, the fire extinction time and the temperature drop range were investigated. In order to reveal the effect of ultrafine dry powder on oxygen content in gas jet, the experiment that spray the compressed nitrogen were conducted. The results show that there are not much differences for the two gases in extinguishing the pool fire, indicating that compressed air as the driving gas of the compound jet is feasible during fire extinguishing process.


Pandemic and Older Adults' Social Structure of Shared Time.
Shared time with family and friends is crucial for older adults' health and well-being. This study examines how a public health crisis affects older adults' social connectedness through their shared time with known persons. The study used data from the 2019-2020 American Time Use Survey (N=9,697) to assess older adults' (aged 50+) social structure of shared time before and during the COVID-19 pandemic. Logistic regression and hurdle model with state fixed effects were used to estimate the relationships between state-level pandemic severity and measures of older adults' shared time, while controlling for sociodemographic characteristics. There were small, statistically significant effects of pandemic severity on older adults' shared time. State-level incidence rates and policy stringency indexes were correlated with a lower likelihood of, and a decline in, older adults' shared time in public places and interactions with individuals outside their immediate family. State policy stringency was associated with more shared time in immediate family interactions. Furthermore, pandemic severity was not associated with a decrease in likelihood and older adults' shared time with non-resident immediate family. Policy stringency was more consequential than incidence rate for older adults' social structure of shared time during the pandemic. Results indicate a place-based and role-based restructuring of older adults' daily shared time during the pandemic. Despite small effect sizes, the substantial old age population implies significant changes in shared time and patterns of daily connection at the population level. Theoretical and policy implications of the findings are discussed.


Brain abscess as an initial presentation in a patient of hereditary haemorrhagic telangiectasia caused by a novel ENG mutation.
Hereditary haemorrhagic telangiectasia (HHT) is a rare inherited autosomal-dominant vascular dysplasia involving multiple organs. Brain abscess is an uncommon and potential fatal complication. We report a case of HHT caused by a novel ENG mutation who initially presented as brain abscess. The patient, with a family history of epistaxis, presented with fever, headache and right-sided haemiparesis. Upon examination, brain MRI showed a contrast-enhanced abscess on the left fronto-parietal region. Open brain drainage was performed and pus culture yielded Actinomyces meyeri. The chest image revealed multiple pulmonary arterio-venous fistulas. HHT was diagnosed according to Curacao criteria. Genetic analysis revealed a novel duplication on exon 6 of ENG gene, which segregates with symptomatic subjects in her family. Clinicians should be cautiously aware of HHT as a differential diagnosis if patients presented with an unknown entry source of intracerebral infections.


Spontaneous resolution of a flow-related ophthalmic-segment aneurysm after treatment of anterior cranial fossa dural arteriovenous fistula.
The natural history of proximal, feeding-artery aneurysms after successful obliteration of high-grade, anterior cranial fossa dural arteriovenous fistulas (dAVFs) has not been well documented. A 52-year-old Caucasian male presented with an unruptured anterior cranial fossa (dAVF) and an associated aneurysm. Cerebral angiography revealed a large, contralateral, carotid-ophthalmic segment aneurysm, enlarged feeding ophthalmic arteries, as well as cortical venous drainage. Successful surgical obliteration of the dAVF was undertaken to eliminate the risk of hemorrhage. The carotid-ophthalmic aneurysm regressed significantly after surgical obliteration of the dAVF and a follow-up, planned coiling procedure to address the carotid-ophthalmic aneurysm was abandoned. This represents the first reported case of a near complete, spontaneous resolution of an unruptured carotid-ophthalmic aneurysm associated with a high-grade anterior cranial fossa dAVF.


A Comparison of Two Analytical Approaches for the Quantification of Neurofilament Light Chain, a Biomarker of Axonal Damage in Multiple Sclerosis.
Neurofilament light chain (NfL), is a neuron-specific cytoskeletal protein detected in extracellular fluid following axonal damage. Extensive research has focused on NfL quantification in CSF, establishing it as a prognostic biomarker of disability progression in Multiple Sclerosis (MS). Our study used a new commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit and Single Molecular Array (Simoa) advanced technology to assess serum NfL levels in MS patients and Healthy Controls (HC). Verifying the most accurate, cost-effective methodology will benefit its application in clinical settings. Blood samples were collected from 54 MS patients and 30 HC. Protocols accompanying the kits were followed. The ELISA thershold was set as 3 S.D. above the mean of the HC. For Simoa, the Z-score calculation created by Jens Kuhle's group was applied (with permission). Samples exceeding the threshold or z-score ≥1.5 indicated subclinical disease activity. To our knowledge, this is the first study to find strong-positive correlation between ELISA and Simoa for the quantification of NfL in serum (r = 0.919). Despite the strong correlation, Simoa has better analytical sensitivity and can detect small changes in samples making it valuable in clinical settings. Further research is required to evaluate whether serum NfL quantification using ELISA could be utilized to predict disability progression.


Novel mating type-dependent transcripts at the mating type locus in Magnaporthe oryzae.
The mating type locus (MAT1) of Magnaporthe oryzae has similar structural organization to MAT in other ascomycetes and encodes the mating type genes MAT1-1-1 with an alpha-box motif and MAT1-2-1 with an HMG-box motif in the MAT1-1 and MAT1-2 idiomorphs, respectively. Sequence and expression analyses of the MAT1 locus indicated a second open reading frame (ORF), MAT1-1-2, in the MAT1-1 idiomorph, and novel mating-type dependent ORFs (MAT1-1-3 and MAT1-2-2) at the locus. The MAT1-1-3 ORF initiated within the MAT1-1 idiomorph while the MAT1-2-2 ORF initiated at the border of the MAT1-2 idiomorph with both ORFs sharing most of their reading frames in the MAT1 flanking region. This suggests that the encoded proteins (MAT1-1-3 and MAT1-2-2) should be similar in their primary structures but can be distinguished by distinct N-termini with amino acids of 1 and 32, respectively, in each mating type. A CT dinucleotide repeat, (CT)n, present in the upstream region of MAT1-1-3, was polymorphic among the isolates.


Immunohistochemical detection of VHS virus in paraffin-embedded specimens of rainbow trout (Oncorhynchus mykiss): the influence of primary antibody, fixative, and antigen unmasking on method sensitivity.
The influence of the primary antibody, the fixative, and the antigen unmasking technique on the method sensitivity of immunohistochemistry as a method for the identification of viral hemorrhagic septicemia (VHS) virus in paraffin-embedded specimens of naturally infected rainbow trout (Oncorhynchus mykiss) was examined. Fish (200-300 g) were collected during an outbreak of VHS. Parallel specimens from liver, spleen, kidney, and brain were fixed by immersion in 10% phosphate-buffered formalin, periodate-lysine-paraformaldehyde (PLP), Bouin's fluid, or absolute ethanol. Virus cultivation was also performed on parallel specimens, and the virus titer (TCID50/ml) was determined. Purified nucleocapsid protein (N-protein) of the virus was incorporated in an artificial antigen substrate polymerized bovine serum albumin), fixed as described above, and embedded in paraffin wax. Microwave unmasking was performed on formalin-, PLP-, and Bouin's fluid-fixed specimens. The presence of virus peptides in situ or N-protein in the artificial antigen substrates was visualized using an immunohistochemical method based on alkaline phosphatase or peroxidase and one polyclonal and five monoclonal polypeptide-specific antibodies. VHS virus was identified in situ in specimens with high virus titers (10(7-8) TCID50/ml) regardless of the fixative and without the need of an unmasking procedure. A pronounced masking effect was observed for the cross-linking formalin and PLP fixatives. Regardless of the primary antibodies used, there was a significantly higher epidemiologic sensitivity (the proportion of virus positive samples that tested positive by immunohistochemistry) using ethanol and Bouin's fluid compared with formalin and PLP (P < 0.05). At 10(5) TCID50/ml, the average sensitivity reached 0.5, and at > or = 10(6) TCID50/ml, sensitivity was 0.9. Unmasking procedures showed a moderate effect and did not result in significantly higher epidemiologic sensitivity (P = 0.17), There was great variation for the different monoclonal antibodies/antigens and fixatives. Sensitivity studies on antigen substrates were in accordance with results of in situ studies that showed the highest sensitivity for ethanol and Bouin's fluid. Virus cultivation was more sensitive than immunohistochemistry. This study showed that the fixative and the primary antibody both influence method sensitivity and that VHS virus antigens concealed during fixation are difficult to reexpose. Immunostaining for VHS virus should be performed with monoclonal antibodies specific for the N-protein, and tissue samples should be fixed in either ethanol or Bouin's fluid. Immunohistochemistry is specific but is less sensitive than virus cultivation. Immunostaining for VHS virus can be a valuable supplement to virus cultivation during acute outbreaks of disease.


The slender ideal and eating disorders: an interdisciplinary "telescope" model.
This paper interprets eating disorders (including anorexia and bulimia) as one (nonfunctional) manifestation, in modern environments, of evolved psychological mechanisms which modulate the standard of feminine bodily attractiveness as a response to economic conditions. Published evidence from anthropology, sociology, and psychology was used to evaluate predictions that (1) where economic independence is possible, women favor a slender standard and (2) where women lack economic power, marriage tends to be favored and the standard becomes more curvaceous. These patterns were tested by correlating U.S. economic data with changing standards of bodily curvaceousness in Vogue and Playboy. Psychological and biological mechanisms by which the slender standard produces anorexia and bulimia were examined. Published evidence and the empirical data suggest that the standard of bodily curvaceousness is determined by the economics of reproduction. These ideas permit integration of the research on eating disorders in several disciplines and suggest many avenues for future enquiry.


Class A GPCRs: Structure, Function, Modeling and Structure-based Ligand Design.
G protein-coupled receptors (GPCRs), especially the class A, are the most heavily investigated drug targets in the pharmaceutical industry. Tremendous efforts have been made by both industry and academia to understand the molecular structure and function of this large family of transmembrane proteins. Our understanding in GPCR activation has evolved from the classical inactive-active two-state model to a complex view of GPCR conformational ensemble associated with multiple interacting partners such as ligands, allosteric modulators, ions and downstream signaling proteins. New drug targets and ligand design strategies are unveiled. Meanwhile, breakthroughs in X-ray crystallography have resulted in high-resolution structures of over 30 GPCRs, providing structural basis for drug design and functional studies. These enabled wide applications of computational approaches in GPCR research that have led to several groundbreaking studies in the last few years. While a large fraction of human GPCRs has yet to be crystallized, homology modeling plays a pivotal role in the simulation of these GPCRs. Here, we review the recent updates on class A GPCR structure and function, with a focus on the applications and perspectives of molecular modeling in GPCR ligand design.


Intracranial extraosseous chondroblastoma simulating meningioma.
Extraosseous chondroblastoma had been reported in different parts of the body but not intracranially. We report a case of a pathologically proven intracranial extraosseous chondroblastoma of the right cavernous sinus in an 18-year-old woman with CT, MR, and conventional angiographic features simulating meningioma.


A case series of non-valvular cardiac aspergillosis in critically ill solid organ transplant and non-transplant patients and systematic review.
Non-valvular cardiac aspergillosis is a rare infection of the pericardium, myocardium or endocardium and is associated with a high mortality. There is a paucity of reports of non-valvular cardiac aspergillosis in critically ill and solid organ transplant (SOT) patients. The majority of cases have been reported in haemato-oncology patients, some of whom have undergone a bone marrow transplant. We describe four cases affected by non-valvular cardiac aspergillosis in the intensive care setting including a systematic review of this extremely rare infection which is associated with high mortality. All four-patients died but presented with varying clinical, radiological and microbiological evidence of the disease. Three patients presented following complications after solid organ transplantation, two in the context of acute liver failure and emergency liver transplant and one several years after a double lung transplant. The last patient presented with necrotising gall stone pancreatitis, multi-organ failure and subsequently a prolonged intensive care unit (ICU) stay. On review of the literature, January 1955 to July 2019, 45 cases were identified, with different risk factors, clinical and radiological manifestations, treatment regimen and outcome. Antemortem diagnosis of cardiac aspergillosis is difficult and rare, with no cases reporting positive blood culture results. Galactomannan serology has poor sensitivity in solid organ transplant patients, further reduced by prophylactic antimicrobial treatment, which is common in the ICU setting especially post-transplant patients. Due to the scarcity of cases, treatment is extrapolated from invasive aspergillosis management, with emphasis on early treatment with combination therapy.


Treatment of common 'life event' traumas.
General practitioners are confronted daily with patients who have experienced distressing 'life events'. Assisting patients through this process can present a significant challenge. This article points to the reactive symptomatology that may be overtly present or concealed in a stressful event and its aftermath reactions, sets the goal of restoring a person's functioning and their self resources, and gives guidelines of what counselling can do for a patient. People who are attempting to cope with a distressing 'life event' or the aftermath of a trauma can be effectively helped by early short term counselling. Although this task may not be one that appeals to the busy GP, many accessible interventions can restore a person's coping capacity and avoid the prospect of a continuing and deepening pathology. Many symptoms will not fit the diagnostic categories usually associated with stress disorders. Some may show impaired social engagement and social phobia; others may describe low self worth, states of unwellness, relationship dissatisfaction and maladjustments in key areas of behaviour. The task is to help the person gain a different perspective on the distressing event, their own capacities and the supportive influences around them.


Efficiency of platelet-rich plasma therapy for healing sports injuries in young athletes.
In recent years, platelet-rich plasma (PRP) therapy has been a subject of controversy in orthopedics field. Our objective was to assess the efficiency of PRP therapy for patients who have suffered grade 2 meniscal lesions and grade 2 anterior cruciate ligament (ACL) lesions, graded by magnetic resonance imaging (MRI). A retrospective observational study was conducted, which included 72 young recreational athletes who had been diagnosed with grade 2 meniscal injury, graded using MRI, that benefited from PRP therapy as an enhancement of the primary treatment, after cast immobilization. The Lysholm score, the pain intensity and the resuming of the physical activity before the PRP treatment and one month after were analyzed. Our study revealed that patients had an improved subjective perception of pain after PRP therapy and an improvement of the Lysholm score. Concurrently, 83.3% of patients could return to sports and daily physical activity. It can be concluded that PRP therapy is a safe, easy to manage treatment, efficient for pain relief and in resuming of sports activities for young recreational athletes who have sustained partial meniscal or ACL tears. In terms of pain relief, it appears that the PRP therapy could be more efficient for young patients with ACL injuries.


[A device for safe handling of vacuum-dried microbes (author's transl)].
By analogous application of the way of packing which is common for the transportation of infectious material (glass tubes in protective covers) in the handling of vaccuum-dried microbes (ampoule within the ampoule) the risk encountered when opening such receptacles may be reduced to an almost complete absence. Technical details are explained by a schematic representation. The method is suitable for the preservation of freeze-dried vaccines. All processes involved in the practical performance of the method which is ready for routine application are considered in detailed instructions for use.


The effects of marijuana exposure on expiratory airflow. A study of adults who participated in the U.S. National Health and Nutrition Examination Study.
Given the inconclusive science on the long-term effects of marijuana exposure on lung function, the increasing tetrahydrocannabinol composition of marijuana over time, and the increasing legal accessibility of the substance, continued investigation is needed. To determine the independent association between recent and chronic marijuana smoke exposure with spirometric parameters of lung function and symptoms of respiratory health in a large cohort of U.S. adults. This is a cross-sectional study of U.S. adults who participated in the National Health and Nutrition Examination Survey cycles from 2007-2008 and 2009-2010, using the data from standardized spirometry and survey questions performed during these years. In the combined 2007-2010 cohort, 59.1% replied that they had used marijuana at least once, and 12.2% had used in the past month. For each additional day of marijuana use in the prior month, there were no changes in percent predicted FEV1 (0.002 ± 0.04%; P = 0.9), but there was an associated increase in percent predicted FVC (0.13 ± 0.03%, P = 0.0001) and decrease in the FEV1/FVC ratio (-0.1 ± 0.04%; P < 0.0001). In multivariable regressions, 1-5 and 6-20 joint-years of marijuana use were not associated with an FEV1/FVC less than 70% (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 0.7-1.6, P = 0.8, and OR = 1.2, 95% CI = 0.8-1.8, P = 0.4, respectively), whereas over 20 joint-years was associated with an FEV1/FVC less than 70% (OR = 2.1; 95% CI = 1.1-3.9; P = 0.02). For each additional marijuana joint-year smoked, there was no associated change in the mean percent predicted FEV1 (0.02 ± 0.02%; P = 1.00), an increase in percent predicted FVC (0.07 ± 0.02%; P = 0.004), and a decrease in FEV1/FVC (-0.03 ± 0.01%; P = 0.02). In a large cross-section of U.S. adults, cumulative lifetime marijuana use, up to 20 joint-years, is not associated with adverse changes in spirometric measures of lung health. Although greater than 20 joint-years of cumulative marijuana exposure was associated with a twofold increased odds of a FEV1/FVC less than 70%, this was the result of an increase in FVC, rather than a disproportional decrease in FEV1 as is typically associated with obstructive lung diseases.


Correlations Between the EGFR Mutation Status and Clinicopathological Features of Clinical Stage I Lung Adenocarcinoma.
Advanced lung cancers with epidermal growth factor receptor (EGFR) exon 19 deletions (Ex19s) and EGFR exon 21 L858R point mutations (Ex21s) exhibit different clinical behavior. However, these differences are unclear in resectable primary lung tumors.The clinicopathological features of 88 (20.9%) Ex19, 124 (29.4%) Ex21, and 198 (46.9%) EGFR wild-type (Wt) clinical stage I primary adenocarcinomas resected between January 1, 2012 and October 31, 2014 were compared by using Chi-square tests, residual error analysis, analysis of variance, and Tukey tests.Ex21 lesions occurred more frequently in women and never-smokers and had a higher tumor disappearance rate (TDR: 59.6% vs 43.9%; P < 0.001) and lower maximum standardized uptake value (maxSUV: 2.0 vs 3.5; P < 0.01) than Wt lesions; Ex19 lesions had intermediate values (52.8% and 2.6). There was a low frequency of vascular invasion in Ex21 lesions (12.1%; P < 0.05) and a high frequency in Wt lesions (22.7%; P < 0.05). Most Ex19 lesions were intermediate-grade adenocarcinoma (lepidic, acinar, and papillary predominant: 73.9%; P < 0.05). Wt and Ex21 lesions were predominately high-grade (micropapillary or solid predominant, mucinous variant) and low-grade (adenocarcinoma in situ and minimally invasive adenocarcinoma) adenocarcinoma, respectively. Wt lesions had smaller lepidic components (42.1% vs 56.3%; P < 0.001) and larger papillary and solid components (papillary: 15.5% vs 9.0%; P < 0.05; solid: 13.2% vs 3.2%; P < 0.001) than Ex21 lesions. Most Ex19 lesions had intermediate component rates.Most Ex21 lesions were low-grade adenocarcinoma with lepidic growth patterns. Wt high-grade adenocarcinomas included solid and papillary components with vascular invasion. Ex19 lesions were intermediate grade between Ex21 and Wt.


Hysteroscopic myomectomy for menorrhagia using Versascope bipolar system: efficacy and prognostic factors at a minimum of one year follow up.
To evaluate the effectiveness of hysteroscopic submucous myomectomy for women with heavy menstrual bleeding (HMB) over a minimum 1-year period and assess prognostic factors associated with treatment success. Prospective observational study set in a university teaching hospital in UK involving 92 women symptomatic of HMB with submucous myomas consecutively recruited between June 2003 and November 2006. Hysteroscopic myomectomy was performed under outpatient local anaesthetic (n=35, 38%) or daycase general anaesthesia (n=57, 62%) using Gynecare Versascope bipolar system. The main outcome measures were: the need for secondary surgical or medical re-intervention, menstrual improvement and patient satisfaction. Other outcome measures include: successful completion of primary resection, type of secondary treatment. Mean follow up was 2.6 years (95% CI 2.3-2.9). Complete fibroid excision was achieved in 66%. Secondary surgical re-intervention was required in 27 (29%) of which 11 (12%) were repeat hysteroscopic myomectomy and 10 (11%) were hysterectomy procedures. Multiple uterine fibroids and adenomyosis were identified in 80% of hysterectomies. At follow up, improved menstrual symptoms and patient satisfaction were reported by 91% and 86%, respectively. Irregular cycle HMB and incomplete fibroid excision were associated with secondary retreatment. Size of the submucous fibroid resected, presence of intramural and subserosal fibroids, or LA vs. GA setting were unrelated to treatment success. HMB with submucous myomas may be successfully treated by completely removing the intracavity myoma component, irrespective of co-existent intramural or subserosal fibroids or size of fibroid resected. This effect remains sustained over at least a 1-2 year period.


Bayesian approach to discovering pathogenic SNPs in conserved protein domains.
The success rate of association studies can be improved by selecting better genetic markers for genotyping or by providing better leads for identifying pathogenic single nucleotide polymorphisms (SNPs) in the regions of linkage disequilibrium with positive disease associations. We have developed a novel algorithm to predict pathogenic single amino acid changes, either nonsynonymous SNPs (nsSNPs) or missense mutations, in conserved protein domains. Using a Bayesian framework, we found that the probability of a microbial missense mutation causing a significant change in phenotype depended on how much difference it made in several phylogenetic, biochemical, and structural features related to the single amino acid substitution. We tested our model on pathogenic allelic variants (missense mutations or nsSNPs) included in OMIM, and on the other nsSNPs in the same genes (from dbSNP) as the nonpathogenic variants. As a result, our model predicted pathogenic variants with a 10% false-positive rate. The high specificity of our prediction algorithm should make it valuable in genetic association studies aimed at identifying pathogenic SNPs.


Noninferior periodic operation of the metabolite producing biological reactor.
The optimal periodic operation of the biological reactor in which the metabolites belonging to Type I or II in Gaden's classification are produced was investigated from the viewpoint of the multiobjective programming problem. In addition to the productivity of the desired product, its concentration and the conversion of the substrate which have a large influence on the performance of the separation process following the fermentation process were adopted as the objective functions. The growth of cells was assumed to be inhibited both by the substrate and the product, and the Luedeking-Piret model was employed for the specific production rate. The optimal periodic operation was determined by use of the optimization method due to Miele. It was clarified that the noninferior set for the periodic operation was generally composed of the repeated batch portion and the repeated fed-batch one.


Flexible, scalable, and efficient targeted resequencing on a benchtop sequencer for variant detection in clinical practice.
The release of benchtop next-generation sequencing (NGS) instruments has paved the way to implement the technology in clinical setting. The need for flexible, qualitative, and cost-efficient workflows is high. We used singleplex-PCR for highly efficient target enrichment, allowing us to reach the quality standards set in Sanger sequencing-based diagnostics. For the library preparation, a modified NexteraXT protocol was used, followed by sequencing on a MiSeq instrument. With an innovative pooling strategy, high flexibility, scalability, and cost-efficiency were obtained, independent of the availability of commercial kits. The approach was validated for ∼250 genes associated with monogenic disorders. An overall sensitivity (>99%) similar to Sanger sequencing was observed in combination with a positive predictive value of >98%. The distribution of coverage was highly uniform, guaranteeing a minimal number of gaps to be filled with alternative methods. ISO15189-accreditation was obtained for the workflow. A major asset of the singleplex PCR-based enrichment is that new targets can be easily implemented. Diagnostic laboratories have validated assays available ensuring that the proposed workflow can easily be adopted. Although our platform was optimized for constitutional variant detection of monogenic disease genes, it is now also used as a model for somatic mutation detection in acquired diseases.


Inpatient audit simplified.
One hospital's audit program identifies the necessary procedures for selecting criteria, performing audits, and conducting follow-up and shows how they can be accomplished most effectively and efficiently. In addition, it shows that a useful emergency department/outpatient audit can be conducted using data from telephone follow-up for the patients.


General Election 2017: influencing the party manifestos.
Amy Waddell, BVA head of media and public affairs, says that following the announcement of a snap General Election, BVA has produced a manifesto for 2017, highlighting 20 key recommendations for the next Government to consider in terms of domestic policy setting as well as throughout Brexit discussions.


Using theories of change to design monitoring and evaluation of community engagement in research: experiences from a research institute in Malawi.
Background: Evaluation of community and public engagement in research is important to deepen understanding of how engagement works and to enhance its effectiveness. Theories of change have been recommended for evaluating community engagement, for their ability to make explicit intended outcomes and understandings of how engagement activities contribute to these outcomes. However, there are few documented examples of using theories of change for evaluation of engagement. This article reports experience of using theories of change to develop a framework for evaluating community engagement in research at a clinical research organisation in Malawi. We describe the steps used to develop theories of change, and the way theories of change were used to design data collection plans. Based on our experience, we reflect on the advantages and challenges of the theory of change approach. Methods: The theories of change and evaluation framework were developed through a series of workshops and meetings between engagement practitioners, monitoring and evaluation staff, and researchers. We first identified goals for engagement, then used 'so that' chains to clarify pathways and intermediate outcomes between engagement activities and goals. Further meetings were held to refine initial theories of change, identify priority information needs, and define feasible evaluation methods. Results: The theory of change approach had several benefits. In particular, it helped to construct an evaluation framework focused on relevant outcomes and not just activities. The process of reflecting on intended goals and pathways also helped staff to review the design of engagement activities. Challenges included practical considerations around time to consider evaluation plans among practitioners (a challenge for evaluation more generally regardless of method), and more fundamental difficulties related to identifying feasible and agreed outcomes. Conclusions: These experiences from Malawi provide lessons for other research organisations considering use of theories of change to support evaluation of community engagement.


Anemia in Chronic Obstructive Pulmonary Disease and the Potential Role of Iron Deficiency.
The purpose of this review is to evaluate the role of anemia on patient outcomes in chronic obstructive pulmonary disease (COPD), the potential contribution that low iron stores may play in this process, and possible treatment considerations. A review of research studies found that anemia is associated with declining functional outcomes, increased health care utilization and costs, and increased mortality in COPD. Associations exist between reduced iron intake and progression of COPD and in reduction of iron status with declining lung function. Currently data are limited on the effects of either treating anemia or utilizing iron supplementation in anemic COPD patients. If iron supplementation might therefore reverse some of the declines that patients experience, then routine screening and treatment may turn out to be an effective, simple and inexpensive intervention. Iron supplementation models utilized in other inflammatory-related disease states were reviewed as a possible starting point to evaluate treatment options in COPD. Future research can be directed to establish best practice standards for the use of iron supplementation in COPD.


Membrane Technologies in Wastewater Treatment: A Review.
In the face of water shortages, the world seeks to explore all available options in reducing the over exploitation of limited freshwater resources. One of the surest available water resources is wastewater. As the population grows, industrial, agricultural, and domestic activities increase accordingly in order to cater for the voluminous needs of man. These activities produce large volumes of wastewater from which water can be reclaimed to serve many purposes. Over the years, conventional wastewater treatment processes have succeeded to some extent in treating effluents for discharge purposes. However, improvements in wastewater treatment processes are necessary in order to make treated wastewater re-usable for industrial, agricultural, and domestic purposes. Membrane technology has emerged as a favorite choice for reclaiming water from different wastewater streams for re-use. This review looks at the trending membrane technologies in wastewater treatment, their advantages and disadvantages. It also discusses membrane fouling, membrane cleaning, and membrane modules. Finally, recommendations for future research pertaining to the application of membrane technology in wastewater treatment are made.


Role of Dictyostelium racE in cytokinesis: mutational analysis and localization studies by use of green fluorescent protein.
The small GTPase racE is essential for cytokinesis in Dictyostelium but its precise role in cell division is not known. To determine the molecular mechanism of racE function, we undertook a mutational analysis of racE. The exogenous expression of either wild-type racE or a constitutively active V20racE mutant effectively rescues the cytokinesis deficiency of racE null cells. In contrast, a constitutively inactive N25racE mutant fails to rescue the cytokinesis deficiency. Thus, cytokinesis requires only the activation of racE by GTP and not the inactivation of racE by hydrolysis of GTP. To determine the spatial distribution of racE, we created a fusion protein with GFP at the amino terminus of racE. Remarkably, GFP-racE fusion protein was fully competent to rescue the phenotype of racE null cells and, therefore, must reside in the same location as native racE. We found that GFP-racE localized to the plasma membrane of the cell throughout the entire cell cycle. Furthermore, constitutively active and inactive GFP-racE fusion proteins also localized to the plasma membrane. We mapped the domain required for plasma membrane localization to the carboxyl-terminal 40 amino acids of racE. This domain, however, is not sufficient to confer racE function onto a closely related GTPase. Taken together, these results suggest that racE functions at the cell cortex but it is not involved in determining the timing or placement of the contractile ring.


Hsa-miR-150-5p inhibits Wnt-β-catenin signaling in human corneal epithelial stem cells.
In our earlier study, we identified hsa-miR-150-5p as a highly expressed miRNA in enriched corneal epithelial stem cells (CESCs). In this study, we aimed to understand the molecular regulatory function of hsa-miR-150-5p in association with the maintenance of stemness in CESCs. The target mRNAs of hsa-miR-150-5p were predicted and subjected to pathway analysis to identify targets for functional studies. Primary cultured limbal epithelial cells were transfected with hsa-miR-150-5p mimic, inhibitor, or scrambled sequence using Lipofectamine 3000. The transfected cells were analyzed to determine (i) their colony-forming potential; (ii) the expression levels of stem cell (SC) markers/transcription factors (ABCG2, NANOG, OCT4, KLF4, and ΔNp63), the differentiation marker (Cx43), and the hsa-miR-150-5p predicted targets (JARID2, INHBA, AKT3, and CTNNB1) by qPCR; and (iii) the expression levels of ABCG2, p63α, Cx43, JARID2, AKT3, p-AKT3, β-catenin, and active β-catenin by immunofluorescence staining and/or western blotting. The ectopic expression level of hsa-miR-150-5p increased the colony-forming potential (8.29% ± 0.47%, p < 0.001) with the ability to form holoclone-like colonies compared with the control (1.8% ± 0.47%). The mimic-treated cells had higher expression levels of the SC markers but reduced expression levels of Cx43 and the targets of hsa-miR-150-5p that are involved in the Wnt-β-catenin signaling pathway. The expression levels of β-catenin and active β-catenin in the inhibitor-transfected cells were higher than those in the control cells, and the localized nuclear expression indicated the activation of Wnt signaling. Our results indicate a regulatory role for hsa-miR-150-5p in the maintenance of CESCs by inhibiting the Wnt signaling pathway.


An Initiative to Improve 30-Day Readmission Rates Using a Transitions-of-Care Clinic Among a Mixed Urban and Rural Veteran Population.
Hospital readmissions in the United States, especially in patients at high-risk, cost more than $17 billion annually. Although care transitions is an important area of research, data are limited regarding its efficacy, especially among rural patients. In this study, we describe a novel transitions-of-care clinic (TOCC) to reduce 30-day readmissions in a Veterans Health Administration setting that serves a high proportion of rural veterans. In this quality improvement initiative we conducted a pre-post study evaluating clinical outcomes in adult patients at high risk for 30-day readmission (Care Assessment Needs score > 85) discharged from the Iowa City Veterans Affairs (ICVA) Health Care System from 2017 to 2020. The ICVA serves 184,000 veterans across 50 counties in eastern Iowa, western Illinois, and northern Missouri, with more than 60% of these patients residing in rural areas. We implemented a multidisciplinary TOCC to provide in-person or virtual follow-up to high-risk veterans after hospital discharge. The main purpose of this study was to assess how TOCC follow-up impacted the monthly 30-day patient readmission rate. The TOCC resulted in a 19.2% relative reduction in 30-day readmission rates in the 12-month postimplementation period compared to the preimplementation period (9.2% vs 11.4%, P = .04). Virtual visits were more popular than in-person visits among both urban and rural veterans. There was no difference in outcomes between these two follow-up options, and both groups had reduced readmission rates compared to non-TOCC follow-up. A multidisciplinary TOCC within the ICVA featuring both virtual and in-person visits reduced the 30-day readmission rate. This reduction was particularly notable among patients with congestive heart failure.


Mycoplasma bovis infections in cattle.
Mycoplasma bovis is a pathogen causing respiratory disease, otitis media, arthritis, mastitis, and a variety of other diseases in cattle worldwide. It is increasingly recognized by the veterinary and livestock communities as having an important impact on the health, welfare, and productivity of dairy and beef cattle. M. bovis diseases can be difficult to diagnose and control because of inconsistent disease expression and response to treatments and vaccines, and large gaps in our understanding of the epidemiology and pathophysiology of these diseases. There are limited data on which to base evidence-based decisions for treatment and control, and the literature contains differing clinical biases and opinions. This document is intended for veterinarians dealing with cattle and is focused on the cattle production systems of North America. The goal of the consensus statement panel was to encourage an evidence-based approach to M. bovis problems. The scientific literature was critically reviewed, including peer-reviewed journal articles and reviews obtained by database searches using the terms "Mycoplasma bovis" or "mycoplasma + cattle." Where other data were lacking, conference proceedings were reviewed as a source of expert opinion.


Polymorphism of winter phenotype in Siberian hamster: consecutive litters do not differ in photoresponsiveness but prolonged acclimation to long photoperiod inhibits winter molt.
The theory of delayed life history effects assumes that phenotype of adult individual results from environmental conditions experienced at birth and as juvenile. In seasonal environments, being born late in the reproductive season affects timing of puberty, body condition, longevity, and fitness. We hypothesized that late-born individuals are more prone to respond to short photoperiod (SP) than early born ones. We used Siberian hamsters Phodopus sungorus, a model species characterized by high polymorphism of winter phenotype. We experimentally distinguished the effect of litter order (first or third) from the effect of exposure to long photoperiod (LP) before winter (3 months or 5 months) by manipulating the duration of LP acclimation in both litters. We predicted that, irrespective of the litter order, individuals exposed to long photoperiod for a short time have less time to gather energy resources and consequently are more prone to developing energy-conserving phenotypes. To assess effect of litter order, duration of acclimation to long days, and phenotype on basal cost of living we measured basal metabolic rate (BMR) of hamsters. Individuals born in third litters had faster growth rates and were bigger than individuals from first litters, but these differences vanished before transfer to SP. Litter order or duration of LP acclimation had no effects on torpor use or seasonal body mass changes, but prolonged acclimation to LP inhibited winter molting both in first and third litters. Moreover, individuals that did not molt had significantly higher BMR in SP than those which molted to white fur. Although one phenotype usually predominated within a litter, littermates were often heterogeneous. We also found that over 10% of individuals presented late response to short photoperiod. Our data indicate that duration of postnatal exposure to LP may define propensity to photoresponsiveness, regardless of the litter in which animal was born. Existence of littermates presenting different phenotypes suggests a prudent reproductive strategy of investing into offspring of varied phenotypes, that might be favored depending on environmental conditions. This strategy could have evolved in response to living in stochastic environment.


Cholinergic stimulation with pyridostigmine protects myocardial infarcted rats against ischemic-induced arrhythmias and preserves connexin43 protein.
We investigated the effects of acute pyridostigmine (PYR) treatment, an acetylcholinesterase inhibitor, on arterial pressure (AP), heart rate (HR), cardiac sympathovagal balance, and the incidence of arrhythmias during the first 4 h after myocardial infarction (MI) in anesthetized rats. Male Wistar rats were implanted with catheters into the femoral artery and vein for AP recordings and drug administration. Rats received the autonomic receptor blockers methyl-atropine (1 mg/kg iv) and propranolol (2 mg/kg iv) at intervals of 15 min, 1 h after saline (n=16) or PYR (0.25 mg/kg iv, n=18), to indirectly assess sympathovagal balance. Acute treatment with PYR increased cardiac vagal (86±7 vs. 44±5 beats/min) and decreased sympathetic tone (-31±8 vs. -69±7 beats/min). Different animals were implanted with ECG electrodes and catheters. A large MI was induced via left coronary artery ligation after basal recordings. Rats received PYR (n=14) or saline (n=14) 10-15 min after MI, and the recordings lasted up to 4 h. In part of the animals, hearts were removed for connexin43 quantification after all procedures. MI elicited a fall in AP (-45±5 mmHg), a progressive rise in HR (26±14 beats/min), and an increase in corrected QT interval (33±13 ms). PYR elicited a prompt bradycardia (-50±14 beats/min) that returned to basal levels over time, and it prevented the lengthening of the corrected QT interval. Treatment with PYR increased by ∼20% the occurrence of rats free of arrhythmias after MI. MI markedly decreased connexin43 in left ventricles, and PYR treatment partially prevented this decrease.


[Therapy of acute and subacute epiphysiolysis of the femur head].
Therapy and prognosis of the slipped capital femoral epiphysis are discussed in connection with the results obtained in the authors' own patients. Reduction of a dislocated femoral head is always desirable. If closed reduction fails, it will be necessary to reduce in full view. In smaller children, fixation is effected by means of several Kirschner wires, in older ones via screw osteosynthesis. Bone pegging or osteotomy are not suited for treatment of an acute or subacute slipped capital epiphysis.


A review on cardiovascular effects of newer hypoglycaemic medications.
Cardiovascular disease (CVD) is the most prevalent cause of morbidity and mortality in diabetic patients. Improvement in cardiovascular complications with glycaemic control and managing cardiovascular risk factors is well established. However, the impact of hypoglycaemic medications on CVD is of increasing importance. In 2008, the U.S. Food and Drug Administration issued study regulations for hypoglycaemic agents after rosiglitazone was shown to increase the incidence of myocardial infarction, and the European Medicines Agency provided their own guidance in 2012. As a result, multiple studies have been published evaluating the cardiovascular safety of newer hypoglycaemic medications. Empagliflozin and liraglutide are among the newer agents that have shown cardiovascular benefit and are now recommended for patients with CVD or are at an increased risk of CVD per the 2017 American Diabetes Association Guidelines. Given the influx of new literature and other ongoing studies, it is important to understand the cardiovascular safety of newer hypoglycaemic medications. The purpose of this article is to provide a comprehensive review of clinical trials conducted evaluating cardiovascular outcomes of newer hypoglycaemic medications and their role within diabetic management. Key Messages With the prevalence of cardiovascular disease in diabetic patients, clinicians should develop a medication regimen that provides both sufficient efficacy for diabetes while also maintaining cardiovascular safety. Of the new diabetic classes, empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and liraglutide, a glucagon-like peptide-1 receptor agonist, have shown cardiovascular benefit in diabetic patients with established cardiovascular disease and are now recommended in current guidelines for this population. Ongoing trials will give more insight to whether cardiovascular benefit is a class effect with sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists and the cardiovascular safety of dipeptidyl peptidase-4 inhibitors.


Cefuroxime-induced lupus.
Drug-induced lupus erythematosus (DILE) is a syndrome that shares symptoms and laboratory characteristics with idiopathic systemic lupus erythematosus. Recognition of DILE is important because it usually reverts within a few weeks after stopping the offending drug. Antibiotics are uncommonly associated with DILE, and cefuroxime has never been incriminated as a cause. We present herein the first case of DILE induced by cefuroxime. Although this is the first report of cefuroxime-induced DILE, we should be aware of this occurrence.


The regulatory role of nickel on H3K27 demethylase JMJD3 in kidney cancer cells.
Nickel compounds are an important class of environmental pollutants and carcinogens. Chronic exposure to nickel compounds has been connected with increased risks of numerous cancers, including lung and kidney cancers. But the precise mechanism by which nickel compounds exert their carcinogenic properties is not completely understood. In this study, kidney cancer cells namely human embryonic kidney 293-containing SV40 large T-antigen (HEK293T) and 786-0 were incubated with various concentrations of nickel chloride for 24 h before analysing the expression of three histone H3K27 methylation-modifying enzymes and H3K27me3 using quantitative real-time polymerase chain reaction, Western blot and immunofluorescence analyses. Our results showed that incubation of nickel chloride upregulated the expression of H3K27me3 demethylase jumonji domain-containing protein 3 (JMJD3) in kidney cancer cells, which was accompanied by the reduction in the protein level of H3K27me3. Enhanced demethylation of H3K27me3 may represent a novel mechanism underlying the carcinogenicity of nickel compounds.


MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis.
The age-related senescence of adult tissues is associated with the decreased level of angiogenic capability and with the development of a degenerative disease such as atherosclerosis which thereafter result in the deteriorating function of multiple systems. Findings indicate that tissue senescence not only diminishes repair processes but also promotes atherogenesis, serving as a double-edged sword in the development and prognosis of ischaemia-associated diseases. Evidence evokes microRNAs (miRNAs) as molecular switchers that underlie cellular events in different tissues. Here, miRNAs would promote new potential targets for optimizing therapeutic methods in blood flow recovery to the ischaemic area. Effectively beginning an ischaemia therapy, a more characteristic of miRNA changes in adult tissues is prerequisite and in the forefront. It may also be a preliminary phase in treatment strategies by stem cell-based therapy.


The International Society for the Study of the Lumbar Spine: research trends over time and publication rates.
A retrospective review was conducted to assess trends in research selected for podium presentation at ISSLS. Abstracts of past papers presented to ISSLS provide quantified documentation of trends in research as well as insight into future directions. A systematic review of abstracts of research presented was performed. Graphical plots in each category of research and aspects of study quality were used to identify any trends. Univariate and multivariate logistical regression analyses were used to identify factors related to eventual publication. A total of 43% of selected papers focused on the disc, representing the single largest area of research. There is a linear trend over time toward increased selection of basic science papers and decreased clinical papers. Experimental research design is becoming more frequently selected. In 1978, over 80% of papers were purely descriptive. By 2002, 42% of papers were descriptive, whereas 40% incorporated an experimental design. However, over the past decade, there has been a linear increase in the proportion of randomized controlled trials among clinical papers compared with basic science or biomechanical papers. A total of 54% of all abstracts presented recently went on to publication. Independent factors that were associated with significantly (P < 0.05) higher publication rates included use of blinded or independent observers (84.6%), experimental design (68.4%), basic science or biomechanical papers (62.3%), and statistically positive result (61.8%). Overall, the type of research selected for presentation at ISSLS has improved over the years in regards to greater use of experimental and randomized study design. The eventual publication rates compare favorably to other research societies. Factors related to publication have been identified and should be considered in future research.


Color Doppler sonographic findings of inflamed and perforated Meckel diverticulum.
To describe color Doppler sonographic findings in 2 cases of inflamed and perforated Meckel diverticulum. Two patients with inflamed and perforated Meckel diverticulum underwent color Doppler sonographic studies. Gray scale sonographic examination identified a fixed cystlike structure with a gut signature surrounded by a hyperechoic layer. Color Doppler sonography revealed hyperemia in the diverticular wall and hyperechoic layer, which was more intense in 1 patient. Identification of a fixed cystlike structure with a gut signature and wall hyperemia suggests the diagnosis of inflamed Meckel diverticulum; when a hyperechoic layer surrounds this structure, perforation of the diverticulum should be suspected.


The etiology of adolescent idiopathic scoliosis.
The etiology of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, is unclear. Researchers with divergent perspectives have tried to better define this etiology. Genetics, growth hormone secretion, connective tissue structure, muscle structure, vestibular dysfunction, melatonin secretion, and platelet microstructure are major areas of focus. In this article, we review the literature in these areas and present the consensus on proposed hypotheses. Studies that simplify the etiology to a single factor have been inconclusive or unsuccessful. Most likely, the etiology is multifactorial, and reported associations are links in pathogenesis rather than etiologic factors. Research is needed to better define the role of all factors in AIS development.


Translesional Fractional Flow Reserve is Related to Plaque Components in Coronary Artery Disease: A Study Combining Pressure Wire and NIRS-IVUS Analysis.
It remains unclear whether atherosclerotic plaque structure or composition is related to translesional biomechanical stresses in coronary artery disease. The aim of this study was to evaluate the association between translesional pressure parameters (using a pressure wire) and plaque characteristics (using a combined near-infrared spectroscopy [NIRS] and intravascular ultrasound [IVUS] imaging catheter). Fractional flow reserve (FFR), delta (Δ) FFR, and Δ pressure were obtained during adenosine-induced maximum hyperemic status. Lipid core burden index (LCBI) and maximum LCBI within 2 mm (maxLCBI2mm) and tomographic anatomy were evaluated by NIRS-IVUS. Sixty-six lesions from 57 patients were analyzed (57 lesions for FFR, 45 lesions for ΔFFR). There was a negative correlation between FFR and maxLCBI2mm (r=-0.264; P=.049) and a positive correlation between ΔFFR and maxLCBI2mm (r=0.299; P=.049). ΔFFR of lesions with maxLCBI2mm ≥500 was significantly higher than maxLCBI2mm <500 (0.159 ± 0.085 vs 0.104 ± 0.075, respectively; P=.04). By receiver-operating characteristic curve analysis, ΔFFR ≥0.1 was a predictor for maxLCBI2mm ≥500 (area under curve, 0.707; 95% confidence interval, 0.552-0.862; P=.03). On multivariate analysis, ΔFFR was the only predictor of maxLCBI2mm (β=0.347; P=.03). ΔFFR across a coronary artery lesion is related to lipid core burden assessed using NIRS-IVUS and might be a meaningful predictor of high-risk plaque (plaque with high lipid content).


Compare Complication of Classic versus Patent Hemostasis in Transradial Coronary Angiography.
Coronary artery disease (CAD) is multifactorial disease, in which thrombotic occlusion and calcification occur usually. New strategies have been made for diagnosis and treatment of CAD, such as transradial catheterization. Hemostasis could be done in two approaches: traditional and patent. Our aim is to find the best approach with lowest complication. In a comparative study, 120 patients were recruited and divided randomly into two subgroups, including traditional group (60 patients; 24 females, 36 males; mean age: 64.35 ± 10.56 years) and patent group (60 patients; 28 females, 32 males; mean age: 60.15 ± 8.92 years). All demographic data including age, gender, body mass index, and CAD-related risk factors (smoking, diabetes, hypertension) and technical data including the number of catheters, procedure duration, and hemostatic compression time and clinical outcomes (radial artery occlusion [RAO], hematoma, bleeding) were collected. Data were analyzed by SPSS version 16. Our findings revealed that the incidence of RAO was significantly lower in patent groups compared with traditional group (P = 0.041). Furthermore, the difference incidence of RAO was higher in early occlusion compare with late one (P = 0.041). Moreover, there were significant relationship between some factors in patients of traditional group with occlusion (gender [P = 0.038], age [P = 0.031], diabetes mellitus [P = 0.043], hemostatic compression time [P = 0.036]) as well as in patent group (age [P = 0.009], hypertension [P = 0.035]). Our findings showed that RAO, especially type early is significantly lower in patent method compared classic method; and patent hemostasis is the safest method and good alternative for classical method.


HHV-8 and AIDS-related CNS lymphoma.
Human herpesvirus 8 (HHV-8), the Kaposi's sarcoma (KS)-associated herpesvirus, is closely related to the transforming Epstein-Barr virus (EBV) and may be detected in AIDS-related, EBV-containing, body-cavity-based lymphomas. Accordingly, we analyzed 27 EBV-positive, AIDS-related CNS lymphomas for HHV-8 sequences. Only one tumor yielded HHV-8 sequences; this tumor arose in a patient with concomitant systemic lymphoma and a history of KS. We conclude that HHV-8 is unlikely to have a major role in the pathogenesis of AIDS-related, EBV-associated CNS lymphomas.


Levels of human tissue kallikrein in the vitreous fluid of patients with severe proliferative diabetic retinopathy.
The aim of this study was to determine the levels of human tissue kallikrein in the vitreous fluid of patients with severe proliferative diabetic retinopathy (PDR). Tissue kallikrein levels were measured using a specific ELISA (range: 0.4-25 ng/ml) in 7 vitreous fluids from eyes with severe PDR. Seven vitreous samples from eyes which underwent vitrectomy because of rhegmatogenous retinal detachment served as non-PDR controls. Enzymatic activity was also tested by an amidolytic assay using a chromogenic substrate. In the PDR patients, vitreous tissue kallikrein was <0.4 ng/ml (5 eyes) or very low (0.52 and 0.58 ng/ml). Vitreous tissue kallikrein was <0.4 ng/ml in all non-PDR controls. These results were confirmed by the amidolytic test. Results suggest that vitreous tissue kallikrein probably plays either a secondary or no role in the pathogenesis of PDR.


Fabrication and characterization of multilayer supermirrors for hard X-ray optics.
Multilayer supermirrors stacked with three sets of Pt/C combinations have been fabricated on a flat float-glass and conical replica foil mirror using a magnetron DC sputtering system, and applied to X-ray optical systems in the hard X-ray region. The design of the supermirror is optimized to obtain the highest integrated reflectivity in the energy band and at the grazing angle concerned. X-ray reflectivities of 30% in the 25-35 keV band at an incidence angle of 0.3 degrees were obtained.


Sociodemographic Patterns of Outpatient Falls: Do Minority Patients Fall Less Frequently?
Falls are the most common cause of injury in the elderly, resulting in $50 billion of annual spending. Social and demographic factors associated with falling are not well understood. We hypothesized minority groups (minority race, lower income, and lower education levels) would experience similar rates of falling to majority groups after adjustment for medical factors. We used the 2013 Medicare Current Beneficiary Survey Public Use File, a representatively sampled cross-sectional survey of Medicare outpatients. Fall was defined as at least one self-reported fall in the previous year. Logistic regression was performed to determine sociodemographic factors (age, sex, race, ethnicity, income, education level, and marital status) associated with fall. Health factors, physical limitations, and cognitive limitations were included as possible confounders. Data are presented as extrapolated weighted population proportions (±SE). 13,924 Medicare beneficiaries, representing 47 million people, were included. 26.6% (±0.4) reported falling. In adjusted logistic regression, black and Hispanic patients had significantly fewer self-reported falls than white patients, after adjustment for medical conditions, physical limitations, and cognitive limitations. Black and Hispanic Medicare patients are significantly less likely to have reported a fall than non-Hispanic whites. This finding differs from other health-related disparities in which minorities most commonly experience higher risk or more severe diseases. These data may also represent differences in self-reporting, indicating disparities in self-reported data in these cohorts. Further studies on social factors related to falling are needed in this population.


Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway.
Activation of intestinal human pregnane X receptor (PXR) has recently been proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. The present study was aimed at evaluating the effect of rifaximin, a non-absorbable antibiotic, in inhibiting angiogenesis in a model of human colorectal epithelium and investigating the role of PXR in its mechanism of action. Caco-2 cells were treated with rifaximin (0.1, 1.0 and 10.0 µM) in the presence or absence of ketoconazole (10 µM) and assessed for cell proliferation, migration and expression of proliferating cell nuclear antigen (PCNA). The release of vascular endothelial growth factor (VEGF) and nitric oxide (NO), expression of Akt, mechanistic target of rapamycin (mTOR), p38 mitogen activated protein kinases (MAPK), nuclear factor κB (NF-κB) and metalloproteinase-2 and -9 (MMP-2 and -9) were also evaluated. Treatment with rifaximin 0.1, 1.0 and 10.0 µM caused significant and concentration-dependent reduction of cell proliferation, cell migration and PCNA expression in the Caco-2 cells vs. untreated cells. Treatment downregulated VEGF secretion, NO release, VEGFR-2 expression, MMP-2 and MMP-9 expression vs. untreated cells. Rifaximin treatment also resulted in a concentration-dependent decrease in the phosphorylation of Akt, mTOR, p38MAPK and inhibition of hypoxia-inducible factor 1-α (HIF-1α), p70S6K and NF-κB. Ketoconazole (PXR antagonist) treatment inhibited these effects. These findings demonstrated that rifaximin causes PXR-mediated inhibition of angiogenic factors in Caco-2 cell line and may be a promising anticancer tool.


Eimeria leuckarti infection in foals.
This is the first report on Eimeria leuckarti infection in foals in Japan. Seven Thoroughbred or Angloarabian foals 2 to 7 months of age raised in the Hidaka district, Hokkaido, were infected with E. leuckarti. They died of severe alterations caused by the larval migration of Strongylus vulgaris, and were examined over a period from 1970 to 1973. Protozoa of this species were observed in the small intestine in all the foals. They were found mostly in vacuoles of the cytoplasm of monoclear cells in the lamina propria at or near the tip of villi. Various stages of gametocytes, oocysts, and microgametocytes were found. In infected cells the nucleus was markedly enlarged, but the cellular response was very slight to the parasite.


Deciphering the Molecular Profile of Lung Cancer: New Strategies for the Early Detection and Prognostic Stratification.
Recent advances in radiological imaging and genomic analysis are profoundly changing the way to manage lung cancer patients. Screening programs which couple lung cancer risk prediction models and low-dose computed tomography (LDCT) recently showed their effectiveness in the early diagnosis of lung tumors. In addition, the emerging field of radiomics is revolutionizing the approach to handle medical images, i.e., from a "simple" visual inspection to a high-throughput analysis of hundreds of quantitative features of images which can predict prognosis and therapy response. Yet, with the advent of next-generation sequencing (NGS) and the establishment of large genomic consortia, the whole mutational and transcriptomic profile of lung cancer has been unveiled and made publicly available via web services interfaces. This has tremendously accelerated the discovery of actionable mutations, as well as the identification of cancer biomarkers, which are pivotal for development of personalized targeted therapies. In this review, we will describe recent advances in cancer biomarkers discovery for early diagnosis, prognosis, and prediction of chemotherapy response.


Partial agonist activity of celiprolol, a cardioselective beta-antagonist.
The beta-antagonistic effects of celiprolol were assessed in isolated guinea-pig preparations. The pA2 values obtained were 7.84 +/- 0.07, 7.79 +/- 0.06 and 6.45 +/- 0.11 against the positive chronotropic and inotropic effects in the atria and relaxant effects in the trachea induced by isoproterenol, respectively, indicating that celiprolol is a cardioselective beta-antagonist. Celiprolol produced slight positive chronotropic and inotropic effects in atrial preparations and a uniquely strong relaxant effect in tracheal preparations. All these effects were attenuated by pretreatment with 10(-6) M atenolol or 10(-6) M propranolol. In pithed rats, celiprolol produced pressor responses at doses lower than 0.03 mg/kg and hypotensive responses at doses higher than 0.3 mg/kg. It produced sustained increases in heart rate in all doses applied. These effects were attenuated by pretreatment with 1 mg/kg of propranolol. The pressor response might be taken to be a reflection of an increase in cardiac function mediated by cardiac beta 1-receptor stimulation, while the hypotension may be ascribed mainly to stimulation of beta 2-adrenoceptors in the vascular system. It is concluded that celiprolol exerts a uniquely strong partial agonist activity at beta 2-adrenoceptors.


Structure Determination of Basic Phospholipase A(2) from the Venom of Agkistrodon halys Pallas in A New Monoclinic Crystal Form.
Basic phospholipase A(2) from the venom of Agkistrodon halys Pallas ( Agkistrodin blomhoffii brevicaudus ) exhibits hemolytic and anti-coagulant activities. A new monoclinic crystal form with four molecules per asymmetric unit was grown in the absence of n-octyl beta-o-glucopyranoside (beta-OG). The enzyme structure was determined by the molecular replacement method. The combined analysis of self- and cross- rotation function was used and non-crystallographic symmetry restraints were imposed to the structure refinement. The final model gave an acceptable crystallographic R factor and reasonable stereochemistry. Two molecules formed an interfacial-recognition-site linked dimer and two such dimers constituted a tetramer having pseudo 222 symmetry. Structural comparison with previously reported monoclinic forms, in which beta-OG was bound, showed that the variation of crystallization conditions had effects on the crystal packing, leading to significant changes of the cell parameters. Nevertheless, the structures of both the dimer and tetramer in the two crystal forms closely resembled to each other, indicating that the oligomers found in the monoclinic crystal forms were stable.


Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA).
In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM.


Serotyping and biotyping of 160 Escherichia coli strains: comparative study.
One hundred and sixty Escherichia coli strains were serotyped and biotyped. Serotyping revealed 68 different types, with 25 strains not typable. Biotyping was possible in all strains but revealed 55 different types. One biotype could be subdivided into 35 different serotypes, indicating that for this biotype the series of biochemical and fermentation reactions could be extended for further differentiation.


[Surgical resection for T4 lung cancer invading thoracic aorta].
The prognosis of the lung cancer patients with aortic invasion is thought to be very poor in general. Thoracic aorta resection and reconstruction was performed in 6 patients, aortic arch in 2, descending aorta in 4. An intraoperative and a postoperative major complication occurred in each 1 patient. Five patients survived more than 1 year after operation, and 1 of them has been living without relapse for more than 5 years. Pulmonary resection with the involved aorta can be done safely using cardiopulmonary bypass, with encouraging long-term survivals in patients without N2 or N3 nodal metastasis.


MMDIT: A tool for the deconvolution and interpretation of mitochondrial DNA mixtures.
Short tandem repeats of the nuclear genome have been the preferred markers for analyzing forensic DNA mixtures. However, when nuclear DNA in a sample is degraded or limited, mitochondrial DNA (mtDNA) markers provide a powerful alternative. Though historically considered challenging, the interpretation and analysis of mtDNA mixtures have recently seen renewed interest with the advent of massively parallel sequencing. However, there are only a few software tools available for mtDNA mixture interpretation. To address this gap, the Mitochondrial Mixture Deconvolution and Interpretation Tool (MMDIT) was developed. MMDIT is an interactive application complete with a graphical user interface that allows users to deconvolve mtDNA (whole or partial genomes) mixtures into constituent donor haplotypes and estimate random match probabilities on these resultant haplotypes. In cases where deconvolution might not be feasible, the software allows mixture analysis directly within a binary framework (i.e. qualitatively, only using data on allele presence/absence). This paper explains the functionality of MMDIT, using an example of an in vitro two-person mtDNA mixture with a ratio of 1:4. The uniqueness of MMDIT lies in its ability to resolve mixtures into complete donor haplotypes using a statistical phasing framework before mixture analysis and evaluating statistical weights employing a novel graph algorithm approach. MMDIT is the first available open-source software that can automate mtDNA mixture deconvolution and analysis. The MMDIT web application can be accessed online at https://www.unthsc.edu/mmdit/. The source code is available at https://github.com/SammedMandape/MMDIT_UI and archived on zenodo (https://doi.org/10.5281/zenodo.4770184).


A group therapist reflects on violence in America.
In this paper, the author draws on his experience as a group therapist, noting parallels between the often intense but well contained dynamics of therapy groups and what they can tell us about violence in America. He examines the tension between bearing and understanding feelings and the desire to act on them, sometimes destructively in therapy groups and in society. He notes the omnipresent desire to find scapegoats rather than bear our own discomforts and notes the same in the abuse through which those in power scapegoat those under their control. Using the ideas of Roche, Volkan, and others, he also notes that current violence emerges from threats to individual or group identities often embedded in unfinished crises in the past, whether in a therapy group or in American society. Unresolved racial tensions reaching into the past is one outstanding example. He concludes noting the important role of reparation and forgiveness in therapy groups and society to slow the forward movement of violence.


Development and evaluation of a generic physiologically based pharmacokinetic model for children.
Clinical trials in children are being encouraged by regulatory authorities in light of the immense off-label and unlicensed use of drugs in the paediatric population. The use of in silico techniques for pharmacokinetic prediction will aid in the development of paediatric clinical trials by guiding dosing regimens, ensuring efficient blood sampling times, maximising therapeutic effect and potentially reducing the number of children required for the study. The goal of this study was to extend an existing physiologically based pharmacokinetic (PBPK) model for adults to reflect the age-related physiological changes in children from birth to 18 years of age and, in conjunction with a previously developed age-specific clearance model, to evaluate the accuracy of the paediatric PBPK model to predict paediatric plasma profiles. The age-dependence of bodyweight, height, organ weights, blood flows, interstitial space and vascular space were taken from the literature. Physiological parameters that were used in the PBPK model were checked against literature values to ensure consistency. These included cardiac output, portal vein flow, extracellular water, total body water, lipid and protein. Five model compounds (paracetamol [acetaminophen], alfentanil, morphine, theophylline and levofloxacin) were then examined by gathering the plasma concentration-time profiles, volumes of distribution and elimination half-lives from different ages of children and adults. First, the adult data were used to ensure accurate prediction of pharmacokinetic profiles. The model was then scaled to the specific age of children in the study, including the scaling of clearance, and the generated plasma concentration profiles, volumes of distribution and elimination half-lives were compared with literature values. Physiological scaling produced highly age-dependent cardiac output, portal vein flow, extracellular water, total body water, lipid and protein values that well represented literature data. The pharmacokinetic profiles in children for the five compounds were well predicted and the trends associated with age were evident. Thus, young neonates had plasma concentrations greater than the adults and older children had concentrations less than the adults. Eighty-three percent, 97% and 87% of the predicted plasma concentrations, volumes of distribution and elimination half-lives, respectively, were within 50% of the study reported values. There was no age-dependent bias for term neonates to 18 years of age when examining volumes of distribution and elimination half-lives. This study suggests that the developed paediatric PBPK model can be used to scale pharmacokinetics from adults. The accurate prediction of pharmacokinetic parameters in children will aid in the development of dosing regimens and sampling times, thus increasing the efficiency of paediatric clinical trials.


Embryonic developmental plasticity in the long-snouted seahorse (Hippocampus reidi, Ginsburg 1933) in relation to parental preconception diet.
The aim of the present study was to investigate the hypothesis that parental periconception nutrition in adult seahorses affects the development and growth of their offspring. We tested the hypothesis that because seahorse embryos develop inside the male's brood pouch, manipulation of the male's diet would affect offspring growth and development independently of the female's diet. Adult males and females were fed separately with either wild-caught crustaceans or commercial aquarium diet for 1 month before conception to influence the periconception environment. Approximately 10000 offspring were obtained from four different treatment groups (Male/Wild or Male/Commercial×Female/Wild or Female/Commercial). Weights, physical dimensions and fatty acid profiles of the newborns were determined. Offspring produced when the males receiving commercial diet were mated with wild-fed females were larger (P<0.05) than those produced by wild-fed males. When both males and females were fed with commercial diet, their offspring were significantly smaller than those from the other treatment groups. When commercial diet-fed females were mated with wild-fed males, the offspring showed distortion of the snout:head length ratio. These results support the view that the preconception diet received by males and females differentially affects embryonic development.


Rainbow trout embryos: advantages and limitations for carcinogenesis research.
Rainbow trout embryos are sensitive to the initiation of neoplasms in various tissues by brief exposures to solutions of water-soluble carcinogens. This characteristic was first demonstrated with the sparingly soluble liver carcinogen, aflatoxin B1 (AFB1). A 30-minute exposure of 21-day-old embryos (embryos hatch in 24-25 days at 12 degrees C) to a 0.5-ppm aqueous solution of AFB1 will result in approximately 65 of the survivors having at least 1 liver tumor, 1 year after treatment. The embryos are responsive to both AFB1 dose and the length of exposure and become increasingly sensitive with increased embryonic age. We have used rainbow trout embryos to demonstrate the hepatocarcinogenicity of other aflatoxin metabolites and precursors; aflatoxicol, aflatoxin G1, versicolorin A, and sterigmatocystin. In addition to mycotoxins, trout embryos are sensitive to several nitrosamine hepatocarcinogens including: dimethylnitrosamine, diethylnitrosamine, nitrosopyrrolidine, and 2,6-dimethylnitrosomorpholine. However, with the highly water-soluble nitrosamines, longer exposure time (up to 24 hr) are required. It is generally accepted that each of the above-named carcinogens requires metabolic activation to the ultimate carcinogenic form. This provides indirect evidence that the trout embryo is capable of cytochrome P-450-mediated metabolism. Finally, trout embryos are sensitive to the direct-acting carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine. This compound produces tumors of the liver, stomach, kidney, and swim bladder, and a pronounced female-to-male sex reversal. Results to date have shown that the trout embryo is a sensitive, convenient, and economical whole animal model system with many distinct advantages for carcinogen testing and research.(ABSTRACT TRUNCATED AT 250 WORDS)