Kinetic analysis of Escherichia coli RNase H using DNA-RNA-DNA/DNA substrates.
The kinetic properties of Escherichia coli ribonuclease H (RNase H) were investigated using oligonucleotide substrates that consist of a short stretch of RNA, flanked on either side by DNA (DNA-RNA-DNA). In the presence of a complementary DNA strand, RNase H cleavage is restricted to the short ribonucleotide stretch of the DNA/RNA heteroduplex. The DNA-RNA-DNA substrate utilized for kinetic studies: (formula; see text) is cleaved at a single site (decreases) in the presence of a complementary DNA strand, to generate (dT)7-(rA)2-OH and p-(rA)2-(dT)9. Anion exchange high performance liquid chromatography was used to separate and quantitate the cleavage products. Under these conditions, RNase H-specific and nonspecific degradation products could be resolved. Kinetic parameters were measured under conditions of 100% hybrid formation (1.2-1.5 molar excess of complementary DNA, T much less than Tm). A linear double reciprocal plot was obtained, yielding a Km of 4.2 microM and a turnover number of 7.1 cleavages per s per RNase H monomer. The kinetic properties of substrate analogs containing varying lengths of RNA (n = 3-5) and 2'-O-methyl modifications were also investigated. Maximal turnover was observed with DNA-RNA-DNA substrates containing a minimum of four RNA residues. Kcat for the rA3 derivative was decreased by more than 100-fold. The Km appeared to decrease with the size of the internal RNA stretch (n = 3-5). No significant difference in turnover number of Km was observed when the flanking DNA was replaced with 2'-O-methyl RNA, suggesting that RNase H does not interact with this region of the heteroduplex.


Interactions of the imidazodiazepine Ro 15-4513 with chemical convulsants.
1. The proconvulsant effects of the imidazodiazepine Ro 15-4513, were investigated in mice by use of intravenous infusion of a variety of convulsant drugs. 2. Dose-response and time course studies of Ro 15-4513 against gamma-aminobutyric acid (GABA) antagonists were performed. On the basis of these studies a maximally effective dose of 5 mg kg-1 was administered 5 min before the determination of seizure thresholds in subsequent experiments. 3. Ro 15-4513 (5 mg kg-1) significantly lowered seizure thresholds to pentylenetetrazole, bicuculline and the convulsant benzodiazepine Ro 5-3663, but failed to alter seizure thresholds to picrotoxin, strychnine, caffeine and quipazine. 4. Ro 15-4513 significantly raised seizure threshold to the benzodiazepine receptor inverse agonist methyl 6,7-dimethoxy-4 ethyl-beta-carboline-3-carboxylate (DMCM). 5. These results are discussed in relation to other studies investigating the proconvulsant and alcohol-antagonizing effects of Ro 15-4513.


[Bioresonance. Main principles of bioresonance and electromagnetic therapy].
Theoretic and practical medical aspects of bioresonance therapy are presented. Resonance frequencies of some organs of the ENT zone were estimated experimentally. The experience with 8-year application of a domestic device Deta-Professional in polypous rhinosinusitis is reviewed.


Validation of the use of the lipophilic thiocyanate anion for the determination of membrane potential in Ehrlich ascites tumor cells.
The utility of the lipophilic anion thiocyanate (SCN-) as a probe for the indirect estimation of the cell membrane potential (Vm) in Ehrlich ascites tumor cells has been evaluated by comparison to direct electrophysiological measurements. SCN accumulation is consistent with first-order uptake into a single, kinetically-identifiable cellular compartment, achieving steady-state distribution in 20-30 min at 22 degrees C. The steady state distribution ratio ([SCN-]e/[SCN-]e) in physiological saline is 0.44 +/- 0.02. Treatment of the cells with propranolol (0.13 mM), an activator of Ca2+ dependent K+ channels, reduces the steady-state distribution ratio to 0.19 +/- 0.02. Conversely, treatment with BaCl2 (10 mM), an antagonist of the pathway, increases the SCN- distribution ratio to 0.62 +/- 0.01. The equilibrium potentials (VSCN) calculated under these conditions are virtually identical to direct electrophysiological measurements of the Vm made under the same conditions. The effect of varying extracellular [K+] ([K+]e) in the presence of constant [Na+]e = 100 mM has also been tested. In control cells, elevation of [K+]e from 6 to 60 mM reduces VSCN from -20.6 +/- 1.0 to -13.2 +/- 1.2 mV. Again, microelectrode measurements give excellent quantitative agreement. Propranolol increases the sensitivity of the cells to varying [K+]e, so that a 10-fold elevation reduces VSCN by approximately 31 mV. BaCl2 greatly reduces this response: a 10-fold elevation in [K+]e yielding only a 4-mV reduction in VSCN. It is concluded that the membrane potential of Ehrlich cells can be estimated accurately from SCN- distribution measurements.


Synaptic membrane proteins as substrates for cyclic AMP-stimulated protein phosphorylation in various regions of rat brain.
Synaptosomal plasma membranes from mammalian brain contain protein kinase activity which phosphorylates endogenous membrane proteins and is stimulated by cyclic AMP. Using polyacrylamide gel electrophoresis it was shown that at least ten proteins in the synaptosomal plasma membrane fraction could be phosphorylated by endogenous cyclic AMP-stimulated protein kinase activity. The number of proteins whose phosphorylation was stimulated by cyclic AMP was strongly influenced by the pH and Mg2+ concentration used in the phosphorylation reaction. A complex pattern of cyclic AMP-stimulated protein phosphorylation was obtained only with synaptosomal plasma membranes and a crude microsomal fraction. Mitochondrial and myelin fractions exhibited no cyclic AMP-stimulated protein kinase activity. Investigation of the distribution of substrates for cyclic AMP-stimulated phosphorylation among various brain regions failed to reveal any regional differences.


The effects of the COVID-19 pandemic on patients with obsessive-compulsive disorder.
Little is known about the impact of the COVID-19 pandemic on obsessive-compulsive disorder (OCD). The main aim of this study was to investigate how the pandemic has affected OCD patients and the relationship between the clinical features and the fear and obsession with COVID-19. A total of 30 consecutive patients with OCD and 30 age-and sex-matched healthy controls were included in this cross-sectional study. Based on retrospective information provided by the patients, we evaluated changes in the severity of their OCD during the pandemic compared to the pre-pandemic period. We compared patients with OCD and healthy subjects using scores obtained from various scales. We found that symptom severity worsened in 60% of OCD patients during the pandemic compared to the pre-pandemic period, remained unchanged in 30%, and improved in 10%. The levels of obsession with COVID-19 were found to be higher in OCD patients than in healthy control subjects. The levels of fear of and obsession with COVID-19 both correlated with the anxiety levels of patients with OCD and healthy controls. Our results suggest that the levels of COVID-19 related fear and obsession are not linked to the severity of OCD, but to anxiety levels. Key pointsObsessive-compulsive symptom severity worsened in 60% of OCD patients in the pandemic.COVID-19 obsession levels were higher in OCD patients than healthy controls.COVID-19 fear levels did not differ between the OCD and healthy control groups.COVID-19 obsession levels were correlated with anxiety severity in OCD and healthy control groups.


Risk Functions of Dolphins and Sea Lions Exposed to Sonar Signals.
Acoustic dose-response functions have been recommended as a means of predicting behavioral impacts on marine mammals from anthropogenic noise exposure. Thirty bottlenose dolphins and fifteen sea lions participated in a controlled exposure study to explore dose-response relationships to the received level of a simulated sonar signal. Both species showed an increase in the probability of response and in the severity of response with increased received levels. Differences in species sensitivity were noted in habituation and the impact of age on responsiveness.


Aortic atresia: morphologic characteristics affecting survival and operative palliation.
A quantitative anatomic study of 54 cardiac specimens with aortic atresia is related to surgical treatment of patients with aortic atresia and hypoplastic left heart syndrome. Coarctation of the aorta was present in 80% of patients with aortic atresia and should influence the extent of aortic arch reconstruction when present. Other associated cardiac defects were uncommon but, when present, may be contraindications to operative palliation because of added complexity of the operation. Anatomic abnormalities of the tricuspid or pulmonary valve were present in 7% of cases and could be important in the outcome of palliative procedures. Natural survival was related to thickness of the right ventricular wall so that selection of those infants with thicker and better functioning right ventricles may improve short-term and long-term operative results in aortic atresia.


Severe fever with thrombocytopenia syndrome virus (SFTSV)-host interactome screen identifies viral nucleoprotein-associated host factors as potential antiviral targets.
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus that causes severe infection in humans characterized by an acute febrile illness with thrombocytopenia and hemorrhagic complications, and a mortality rate of up to 30%. Understanding on virus-host protein interactions may facilitate the identification of druggable antiviral targets. Herein, we utilized liquid chromatography-tandem mass spectrometry to characterize the SFTSV interactome in human embryonic kidney-derived permanent culture (HEK-293T) cells. We identified 445 host proteins that co-precipitated with the viral glycoprotein N, glycoprotein C, nucleoprotein, or nonstructural protein. A network of SFTSV-host protein interactions based on reduced viral fitness affected upon host factor down-regulation was then generated. Screening of the DrugBank database revealed numerous drug compounds that inhibited the prioritized host factors in this SFTSV interactome. Among these drug compounds, the clinically approved artenimol (an antimalarial) and omacetaxine mepesuccinate (a cephalotaxine) were found to exhibit anti-SFTSV activity in vitro. The higher selectivity of artenimol (71.83) than omacetaxine mepesuccinate (8.00) highlights artenimol's potential for further antiviral development. Mechanistic evaluation showed that artenimol interfered with the interaction between the SFTSV nucleoprotein and the host glucose-6-phosphate isomerase (GPI), and that omacetaxine mepesuccinate interfered with the interaction between the viral nucleoprotein with the host ribosomal protein L3 (RPL3). In summary, the novel interactomic data in this study revealed the virus-host protein interactions in SFTSV infection and facilitated the discovery of potential anti-SFTSV treatments.


Effect of normobaric oxygen on tumor radiosensitivity: fractionated studies.
The sensitizing ability of 100% normobaric oxygen was investigated in a mouse mammary carcinoma (CaNT) using a variety of fractionated regimens. Both regrowth delay and local control were used as assays of tumor response. With both assays, there was a similar and significant increase in radiosensitivity for all fractionated schedules. Enhancement ratios ranged from 1.24 to 1.45, the highest increase being observed with a 30 fraction schedule given in an overall time of 6 weeks. Thus, in CaNT tumors normobaric oxygen is a far more efficient radiosensitizer in fractionated treatments than the oxygen-mimetic compound misonidazole; an oxygen effect being observed at doses per fraction as low as 1.8 Gy. These results suggest strongly that normobaric gases could play an important role in the clinical management of tumors where hypoxia may limit the outcome of radiotherapy.


Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling.
Knowledge of number, size and content of insulin secretory granules is pivotal for understanding the physiology of pancreatic beta cells. Here we re-evaluated key structural features of rat beta cells, including insulin granule size, number and distribution as well as cell size. Electron micrographs of rat beta cells fixed either chemically or by high-pressure freezing were compared using a high-content analysis approach. These data were used to develop three-dimensional in silico beta cell models, the slicing of which would reproduce the experimental datasets. As previously reported, chemically fixed insulin secretory granules appeared as hollow spheres with a mean diameter of ∼350 nm. Remarkably, most granules fixed by high-pressure freezing lacked the characteristic halo between the dense core and the limiting membrane and were smaller than their chemically fixed counterparts. Based on our analyses, we conclude that the mean diameter of rat insulin secretory granules is 243 nm, corresponding to a surface area of 0.19 μm(2). Rat beta cells have a mean volume of 763 μm(3) and contain 5,000-6,000 granules. A major reason for the lower mean granule number/rat beta cell relative to previous accounts is a reduced estimation of the mean beta cell volume. These findings imply that each granule contains about twofold more insulin, while its exocytosis increases membrane capacitance about twofold less than assumed previously. Our integrated approach defines new standards for quantitative image analysis of beta cells and could be applied to other cellular systems.


Exogenous GH-releasing hormone increases GH and LH secretion in growing mithuns (Bos frontalis).
To investigate the effects of growth hormone-releasing hormone (GHRH) administration on the patterns of GH and LH secretion in growing female mithuns, 12 mithuns within the age group of 10-12 months of age were divided into two groups (treatment and control groups) of six each in such a way that average body weight between the groups did not differ significantly (P>0.05). Both the groups were administered i.v. either with synthetic bGHRH [bGHRH (1-44)-NH2] at 10 microg/100 kg body weight (treatment group) or equal volume of normal saline (control group). Blood samples collected prior to and after GHRH challenge at -60, -45, -30, -15, -10, -5 min and 5, 10, 15, 30 min, and thereafter, at an interval of 15 min up to 8 h post-injection were assayed for plasma GH and LH. Plasma progesterone was estimated in twice-a-week samples collected for six consecutive weeks preceding GHRH challenge to assess whether either group has begun ovarian cyclicity. Body weight of all animals was recorded once in a week during the period. A peak of GH was registered in all animals within 5-25 min post-GHRH administration with a mean peak of 443.5+/-25.32 ng/ml at 15 min post-administration, which was much higher than in any other bovines reported following GHRH challenge. The patterns of LH secretion were pulsatile in nature in both the groups. Interestingly, the hormone concentrations exhibited higher pulsatility with greater amplitude after GHRH challenge in GHRH-treated than in control mithuns. The GHRH-treated mithuns averaged 0.44 pulses/h (4 pulses/9 h) and the rate was 0.20/h (2 pulses/9 h) in controls. The rate of pulse frequency and amplitude differed significantly with time of sampling. The mean plasma LH levels after GHRH administration were significantly higher in treatment group than those recorded in control mithuns. The mean plasma progesterone was similar (P>0.05) in both the groups and no animal from either group had begun ovarian cycle. In conclusion, exogenous GHRH significantly increases plasma GH and also LH pulse frequency and amplitude with higher mean post-GHRH LH levels in growing mithuns suggesting thereby its possible use for enhancement of maturity process in this unique meat animal.


Intravascular ultrasound study of patterns of calcium in ruptured coronary plaques.
Coronary calcium is intimately associated with coronary atherosclerotic plaque development, although it is controversial as to whether coronary calcium is associated with plaque instability. We analyzed 101 IVUS-detected ruptured plaques and compared them with 101 computer-matched control plaques without evidence of plaque rupture. The arc of calcium was measured every 0.5 mm within 10-mm-long segments that spanned the minimum lumen cross-sectional area, and the number and length of calcium deposits were assessed. Ruptured plaques had a significantly larger number of individual calcium deposits than control plaques (3.5 +/- 1.7 vs 1.8 +/- 1.1, p <0.001). However, the arc of the largest calcium deposit was smaller and the length of the largest calcium deposit in each plaque was shorter in ruptured plaques compared with control plaques (67.3 degrees +/- 41.4 degrees vs 114.9 degrees +/- 77.4 degrees , p <0.001, and 1.6 +/- 1.3 vs 4.0 +/- 2.7 mm, p <0.001, respectively). There was no difference in the number of superficial calcium deposits between the 2 groups, although ruptured plaques had significantly smaller arcs of superficial calcium compared with control plaques (56.2 degrees +/- 35.5 degrees vs 95.8 degrees +/- 65.2 degrees , p <0.001). Conversely, the number of deep calcium deposits was significantly larger in ruptured plaques than in control plaques (1.8 +/- 1.4 vs 0.3 +/- 0.6, p <0.001), although the arc of deep calcium was similar in the 2 groups. Ruptured plaques had quantitatively less calcium, especially superficial calcium, but a larger number of small calcium deposits, especially deep calcium deposits. In conclusion, ruptured plaques are associated with a larger number of calcium deposits within an arc of <90 degrees , a larger number of deep calcium deposits, and a remodeling index.


Flexion relaxation of erector spinae response to spinal shrinkage.
The purpose of the study was to investigate the effect of spinal shrinkage on the characteristic of flexion relaxation phenomenon in erector spinae muscle. Twelve male university students volunteered for this study. The spinal shrinkage was created with a load of 20% body weight on shoulder in 10 min. Each performed three trials of lumbar flexion-extension with the cycle of 5s flexion and 5s extension in standing before and after shrinkage. Surface electromyography from right erector spinae muscle as well as trunk flexion performance was recorded synchronously in video camera. A one-way ANOVA with repeated measures was used to evaluate the effect of shrinkage. The results showed that there was a significant (p<0.001) stature change with mean magnitude of shrinkage 5.9 mm. The erector spinae was active through a significantly larger angle during flexion and began activity significantly earlier during extension after shrinkage. It was concluded that shrinkage caused by prolonged compressive loading will elicit the change of flexion relaxation characteristic, which may be closely related to low back disorder.


Does the Angle of Rigid Endoscope Makes a Difference in Videolaryngoscopy.
Authors describe the technique of office based rigid video laryngoscopy with 0° endoscope and compare with technique of 70° 4 mm videolaryngoscopy. (1) To compare and assess the efficacy of techniques of 0° and 70° office based video laryngoscopy for examining laryngopharyngeal disorders at Ear Nose Throat (ENT) Out Patient Department level. (2) To assess whether the degree of angle of the rigid endoscope makes any difference in the visualisation in videolaryngoscopy. Prospective non randomised double blinded study of direct videolaryngoscopies using 0° and 70° 4 mm rigid endoscope (Karl Storz, Germany) done at M.I.M.E.R. Medical College and Sushrut ENT Hospital, Talegaon-D, Pune, India, during the period of October 2016 to February 2017. Patients with predominant complaints of change of voice and foreign body sensation in throat were subjected for Videolaryngoscopy by 0° and 70° 4 mm Endoscope. 375 patients were examined with both the techniques. After the end of the procedure, the patient preference or discomfort with any of the techniques was enquired. The unlabelled endoscopic recording of both techniques was visualised by the second author to compare and evaluate the 0° videolaryngoscopy with 70° in terms of extent of visualisation. The time taken for each technique was recorded. The data of all patients has been analysed in terms of patient and surgeon grading. On statistical analysis, both the techniques with 0° as well as 70° rigid endoscope videolaryngoscopy were found to be comparable. Our study concludes that both the endoscopes are equally efficient in comparable laryngeal visualization. Hence, the degree of angulation of the rigid endoscope makes no difference in videolaryngoscopy. With little practice, 0° videolaryngoscopy may be extended for routine use in laryngological examination. Level of Evidence Level 4.


Low-dose COVID-19 CT Image Denoising Using CNN and its Method Noise Thresholding.
Noise in computed tomography (CT) images may occur due to low radiation doses. Hence, the main aim of this paper is to reduce the noise from low-dose CT images so that the risk of high radiation dose can be reduced. The novel coronavirus outbreak has ushered in different new areas of research in medical instrumentation and technology. Medical diagnostics and imaging are one of the ways in which the area and level of infection can be detected. COVID-19 attacks people with less immunity, so infants, kids, and pregnant women are more vulnerable to the infection. So, they need to undergo CT scanning to find the infection level. But the high radiation diagnostic is also fatal for them, so the intensity of radiation needs to be reduced significantly, which may generate the noise in the CT images. This paper introduces a new denoising technique for low-dose Covid-19 CT images using a convolution neural network (CNN) and noise-based thresholding method. The major concern of the methodology for reducing the risk associated with radiation while diagnosing. The results are evaluated visually and using standard performance metrics. From comparative analysis, it was observed that proposed works give better outcomes. The proposed low-dose COVID-19 CT image denoising model is therefore concluded to have a better potential to be effective in various pragmatic medical image processing applications in noise suppression and clinical edge preservation.


Allelic variations of ClACO gene improve nitrogen uptake via ethylene-mediated root architecture in watermelon.
The ClACO gene encoding 1-aminocyclopropane-1-carboxylate oxidase enabled highly efficient 15N uptake in watermelon. Nitrogen is one of the most essential nutrient elements that play a pivotal role in regulating plant growth and development for crop productivity. Elucidating the genetic basis of high nitrogen uptake is the key to improve nitrogen use efficiency for sustainable agricultural productivity. Whereas previous researches on nitrogen absorption process are mainly focused on a few model plants or crops. To date, the causal genes that determine the efficient nitrogen uptake of watermelon have not been mapped and remains largely unknown. Here, we fine-mapped the 1-aminocyclopropane-1-carboxylate oxidase (ClACO) gene associated with nitrogen uptake efficiency in watermelon via bulked segregant analysis (BSA). The variations in the ClACO gene led to the changes of gene expression levels between two watermelon accessions with different nitrogen uptake efficiencies. Intriguingly, in terms of the transcript abundance of ClACO, it was concomitant with significant differences in ethylene evolutions in roots and root architectures between the two accessions and among the different genotypic offsprings of the recombinant BC2F1(ZJU132)-18. These findings suggest that ethylene as a negative regulator altered nitrogen uptake efficiency in watermelon by controlling root development. In conclusion, our current study will provide valuable target gene for precise breeding of 'green' watermelon varieties with high-nitrogen uptake efficiencies.


A critical evaluation of the environmental risk assessment for plasticizers in the freshwater environment in Europe, with special emphasis on bisphenol A and endocrine disruption.
Bisphenol A (BPA) and the phthalates di-butyl phthalate (DBP), di-ethylhexyl phthalate (DEHP), di-isodecyl phthalate (DIDP) and di-isononyl phthalate (DINP) are high production volume plasticizers and are regularly detected in aquatic ecosystems due to their continuous release into the environment. These compounds are listed as priority substances in the European Union and therefore subject to an environmental risk assessment (ERA). Final ERA reports are available for DBP, DIDP and DINP, while the process is still ongoing for BPA and DEHP. The current approach critically reviews the exposure and especially the effect analyses in the reports or drafts, considering also potential endocrine effects of the plasticizers.


Short term priming effect of brain-actuated muscle stimulation using bimanual movements in stroke.
Brain-computer interface triggered-functional electrical stimulation (BCI-FES) is an emerging neurorehabilitation therapy post stroke, mostly for the affected hand. We explored the feasibility of a bimanual BCI-FES and its short-term priming effects, i.e. stimuli-induced behaviour change. We compared EEG parameters between unimanual and bimanual movements and differentiated the effect of age from the effect of stroke. Ten participants with subacute stroke, ten age-matched older healthy adults, and ten younger healthy adults underwent unimanual and bimanual BCI-FES sessions. Delta alpha ratio (DAR) and brain symmetry index (BSI) were derived from the pre- and post- resting-state EEG. Event-related desynchronization (ERD) and laterality index were derived from movement- EEG. Participants were able to control bimanual BCI-FES. ERD was predominantly contralateral for unimanual movements and bilateral for bimanual movements. DAR and BSI only changed in healthy controls. Baseline values indicated that DAR was affected by stroke while BSI was affected by both age and stroke. Bimanual BCI control offers a larger repertoire of movements, while causing the same short-term changes as unimanual BCI-FES. Prolonged practice may be required to achieve a measurable effect on DAR and BSI for stroke. Bimanual BCI-FES is feasible in people affected by stroke.


Syphilus.
This paper recounts the history of the origin of the term syphilis and presents a partial translation of Fracastoro's poem, Syphilis, Sive Morbus Gallicus, wherein the word first appeared. The circumstances of the first known great epidemic of syphilis are told.


Renal medullary carcinoma: rhabdoid features and the absence of INI1 expression as markers of aggressive behavior.
Renal medullary carcinoma is a rare, well-recognized highly aggressive tumor of varied histopathology, which occurs in young patients with sickle cell trait or disease. Rhabdoid elements, occasionally seen in high-grade renal tumors including renal medullary carcinoma, possibly represent a pathologic marker of aggressive behavior. INI1 (hSNF5/SMARCB1/BAF47) is a highly conserved factor in the ATP-dependent chromatin-modifying complex. Loss of this factor in mice results in aggressive rhabdoid tumors or lymphomas. In humans, the loss of INI1 expression has been reported in pediatric renal rhabdoid tumors, central nervous system atypical teratoid/rhabdoid tumors and epithelioid sarcomas, a possible primary soft tissue rhabdoid tumor. This study compares five renal medullary carcinomas with 10 high-grade renal cell carcinomas (five with rhabdoid features), two urothelial carcinomas and two pediatric renal rhabdoid tumors. All five renal medullary carcinomas, irrespective of histopathology, showed complete loss of INI1 expression similar to that seen in pediatric renal rhabdoid tumors. In contrast, all renal cell carcinomas or urothelial carcinomas, including those with histological rhabdoid features, expressed INI1. Clinically, all five of the patients with renal medullary carcinoma and the two patients with rhabdoid tumors presented with extra-renal metastases at the time of diagnosis. This study demonstrates that renal medullary carcinoma and renal rhabdoid tumor share a common molecular/genetic alteration, which is closely linked to their aggressive biological behavior. However, the absence of INI1 expression is not necessarily predictive of rhabdoid histopathology but remains associated with aggressive behavior in renal medullary carcinoma.


Energetics studies of muscles of different types.
31P-NMR studies were performed in isolated perfused striated and smooth muscles. Important qualitative and quantitative differences were found in resting muscles. In resting fast-twitch skeletal muscle the chemical potential of ATP obtained from the measured intracellular pH, ATP and inorganic phosphate concentrations and from the ADP concentrations calculated from the position of the creatine kinase equilibrium was -72 kJ/mol ATP. This high value was the result of a very low free ADP and inorganic phosphate content. In resting slow-twitch skeletal muscle, in smooth muscle, and in cardiac muscle at low work rates (literature data), the chemical potential of ATP was lower (approximately -50 to -60 kJ/mol), the difference being primarily due to a much higher inorganic phosphate content (especially in slow-twitch and smooth muscle) and/or a higher ADP concentration (especially in cardiac muscle). Upon stimulation or, for the heart, working at higher work rates, the pattern of chemical changes of phosphocreatine, creatine and inorganic phosphate was the same for all types of muscle. The phosphocreatine levels decreased and the inorganic phosphate concentration increased stoichiometrically without a change in the ATP content so long as the phosphocreatine pool was not totally depleted (greater than or equal to 10%). The rate and extent of these chemical changes was dependent on the inherent ATPase and ATP synthesis rates. The exception was in the intracellular pH changes. In fast-twitch and smooth muscle, pH decreased with contractile activity, as expected from the large glycolytic capacity. However, an alkalinization was observed in slow-twitch skeletal muscle and this difference was attributed to the uptake of H+ during the net hydrolysis of phosphocreatine to creatine plus inorganic phosphate, and to the absence of significant lactate production. The pH of cardiac muscle does not appear to change with work load. The common bioenergetic pattern in all types of muscles is consistent with a graded increase in ADP concentration (from below to well above the apparent Km for nucleotide translocase ANT) with increasing work as a regulator of mitochondrial respiration. In fast-twitch muscle these changes are also accompanied by large changes in inorganic phosphate concentration (3-30 mM) which may also play a role in metabolic regulation.(ABSTRACT TRUNCATED AT 400 WORDS)


Cysteamine Enhances Biofilm Eradication Efficacy of Calcium Hydroxide.
Calcium hydroxide (Ca[OH]2) is a widely used interappointment dressing, but its antibacterial property is compromised by dentin. Hence, the addition of chlorhexidine (CHX) with Ca(OH)2 has been proposed. However, the antimicrobial efficacy of this mixture compared with Ca(OH)2 alone is currently still debatable. Cysteamine is a mucolytic agent used to reduce the viscosity of mucus through the disruption of proteins, which are also important components of the extracellular matrix of biofilms. The aims of this study were to determine the efficacy of cysteamine alone and in combination with Ca(OH)2 to eradicate Enterococcus faecalis biofilm compared with CHX with Ca(OH)2, and to determine if this effect is affected by dentin. The biofilm eradication efficacies of Ca(OH)2 alone and with cysteamine were determined using 7-day E. faecalis biofilm cultured on dentin discs and compared with Ca(OH)2 with 2% CHX. The effects of dentin on the efficacies of Ca(OH)2 alone and with either cysteamine or CHX were examined. Cysteamine alone completely abolished E. faecalis biofilm at 200 mg/mL. The combination of Ca(OH)2 with either cysteamine at 10 mg/mL or 2% CHX completely obliterated E. faecalis biofilm. Cysteamine with Ca(OH)2 completely eradicated E. faecalis biofilm despite preincubation with dentin, whereas CHX with Ca(OH)2 was less effective. Cysteamine effectively eliminated E. faecalis biofilm and showed synergistic effects in combination with Ca(OH)2, which were unaffected by dentin. Hence, our findings support the use of cysteamine as a potential adjunct to Ca(OH)2 as an interappointment dressing.


Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient cyclooxygenase-2.
Previous studies have shown that injury initiated by toxicants progresses even after most of the toxicant is eliminated from the body. One mechanism of progression of injury is the extracellular appearance of hydrolytic enzymes following leakage or upon cell lyses. Under normal conditions, after exposure to low to moderate doses of toxicants, secretory phospholipase A(2) (sPLA(2)) and other hydrolytic enzymes are known to appear in the extracellular spaces in order to cleanup the post-necrotic debris in tissues. We tested the hypothesis that sPLA(2) contributes to progression of toxicant-initiated liver injury because of hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas in the absence of sufficient cyclooxygenase-2 (COX-2). Male Sprague-Dawley rats were administered either a moderately hepatotoxic dose (MD, 2 ml CCl(4)/kg, ip) or a highly hepatotoxic dose (HD, 3 ml CCl(4)/kg, ip) of CCl(4). After MD, liver sPLA(2) and COX-2 were co-localized in the necrotic and perinecrotic areas and their activities in plasma and liver increased before decreasing in tandem with liver injury (ALT and histopathology) leading to 100% survival. In contrast, after the HD, high extracellular and hepatic sPLA(2) activities were accompanied by minimal COX-2 activity and localization in the liver throughout the time course. This led to progression of liver injury and 70% mortality. These data suggested a destructive role of sPLA(2) in the absence of sufficient COX-2. Time- and dose-dependent destruction of hepatocytes by sPLA(2) in isolated hepatocyte incubations confirmed the destructive ability of sPLA(2) when present extracellularly, suggesting its ability to spread injury in vivo. These findings suggest that sPLA(2), secreted for cleanup of necrotic debris upon initiation of hepatic necrosis, requires the co-presence of sufficiently induced COX-2 activity to prevent the run-away destructive action of sPLA(2) in the absence of the tissue protective mechanisms afforded by COX-2 induction.


Multifaceted roles of MAGOH Proteins.
MAGOH and MAGOHB are paralog proteins that can substitute each other in the exon junction complex (EJC). The EJC is formed of core components EIF4A3, RBM8A, and MAGOH/MAGOHB. As a part of the EJC, MAGOH proteins are required for mRNA splicing, export, translation and nonsense-mediated mRNA decay (NMD). MAGOH is also essential for embryonic development and normal cellular functioning. The haploinsufficiency of MAGOH results in disorders such as microcephaly and cancer. The present review discusses the discovery of MAGOH, its paralog MAGOHB, their roles in cellular function as part of the EJC, and other cellular roles that are not directly associated with mRNA processing. We also discuss how MAGOH haploinsufficiency in cancer cells can be exploited to develop a novel targeted cancer treatment.


Pulmonary function and expiratory flow limitation in acute cervical spinal cord injury.
To identify the nature of the changes of respiratory mechanics in patients with middle cervical spinal cord injury (SCI) and their correlation with posture. Clinical trial. Acute SCI unit. Patients with SCI (N=34) at C4-5 level studied within 6 months of injury. Patients were assessed by the negative expiratory pressure test, maximal static respiratory pressure test, and standard spirometry. The following respiratory variables were recorded in both the semirecumbent and supine positions: (1) tidal expiratory flow limitation (TEFL); (2) airway resistances; (3) mouth occlusion pressure developed 0.1 seconds after occluded inspiration at functional residual capacity (P(0.1)); (4) maximal static inspiratory pressure (MIP) and maximal static expiratory pressure (MEP); and (5) spirometric data. TEFL was detected in 32% of the patients in the supine position and in 9% in the semirecumbent position. Airway resistances and P(0.1) were much higher compared with normative values, while MIP and MEP were markedly reduced. The ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%, while the other spirometric data were reduced up to 30% of predicted values. Patients with middle cervical SCI can develop TEFL. The presence of TEFL, associated with increased airway resistance, could increase the work of breathing in the presence of a reduced capacity of the respiratory muscles to respond to the increased load. The semirecumbent position and the use of continuous positive airway pressure can be helpful to (1) reduce the extent of TEFL and avoid the opening/closure of the small airways; (2) decrease airway resistance; and (3) maintain the expiratory flow as high as possible, which aids in the removal of secretions.


In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery.
In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or Cmax compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol Cmax and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate.


[Mu-1kappa2O,O':2(eta5)-Cyclopentadienylcarboxylato][2(eta5)-diphenylphosphinocyclopentadienyl]bis[1,1(eta5)-tetramethylcyclopentadienyl]iron(II)titanium(III).
Reacting stoichiometric amounts of 1-(diphenylphosphino)ferrocenecarboxylic acid and [Ti(eta(5)-C(5)HMe(4))(2)(eta(2)-Me(3)SiC[triple-bond]CSiMe(3))] produced the title carboxylatotitanocene complex, [[mu-1kappa(2)O,O':2(eta(5))-C(5)H(4)CO(2)][2(eta(5))-C(5)H(4)P(C(6)H(5))(2)][1(eta(5))-C(5)H(CH(3))(4)](2)Fe(II)Ti(III)] or [FeTi(C(9)H(13))(2)(C(6)H(4)O(2))(C(17)H(14)P)]. The angle subtended by the Ti/O/O' plane, where O and O' are the donor atoms of the kappa(2)-carboxylate group, and the plane of the carboxyl-substituted ferrocene cyclopentadienyl is 24.93(6) degree.


Glycerol-treated nuclear suspensions--an efficient preservation method for flow cytometric analysis of plant samples.
Flow cytometry (FCM) has been widely used in plant science to determine the amount of nuclear DNA, either in absolute units or in relative terms, as an indicator of ploidy. The requirement for fresh material in some applications, however, limits the value of FCM in field research, including plant biosystematics, ecology and population biology. Dried plant samples have proven to be a suitable alternative in some cases (large-scale ploidy screening) although tissue dehydration is often associated with a decrease in the quality of FCM analysis. The present study tested, using time-scale laboratory and in situ field experiments, the applicability of glycerol-treated nuclear suspension for DNA flow cytometry. We demonstrate that plant nuclei preserved in ice-cold buffer + glycerol solution remain intact for at least a few weeks and provide estimates of nuclear DNA content that are highly comparable and of similar quality to those obtained from fresh tissue. The protocol is compatible with both DAPI and propidium iodide staining, and allows not only the determination of ploidy level but also genome size in absolute units. Despite its higher laboriousness, glycerol-preserved nuclei apparently represent the most reliable way of sample preservation for genome size research. We assume that the protocol will provide a vital alternative to other preservation methods, especially when stringent criteria on the quality of FCM analysis are required.


Lipidomics: an analysis of cellular lipids by ESI-MS.
Recognition of the importance of lipid signaling in cellular function has led to rapid progress in the technology of lipid analysis. Measurements of lipid species changes are central to defining the networks of cell signaling (e.g., receptor activation by hormones or drugs) and lipids are involved in many biochemical and pathological processes. During the last several years our laboratory has focused on developing efficient methods for extraction of glycerophospholipids from biological systems and their detection and identification by mass spectrometry. We analyze phospholipid changes in mammalian cells as a result of a defined ligand stimulation strategy that supports the research questions of the consortium. The improvement of mass spectrometry techniques for phospholipid analysis combined with sophisticated computational methods developed in our group has facilitated simultaneous analysis of hundreds of phospholipid species in mammalian cells. This information is presented as Lipid Arrays (or more precisely as virtual arrays) and allows identification of temporal changes in membrane phospholipid species between two contrasting biological conditions (e.g., unstimulated basal vs. stimulated or as a contrast between normal and disease stages). Using the lipidomics approach, we are able to identify approximately 450 phospholipid species from total membrane extracts and qualitatively measure pattern response changes initiated by cell surface receptors. As such, this approach facilitates the elucidation of the metabolic changes induced by a perturbation in the cell and recognition of patterns of signaling.


Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms.
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.


Lack of effect of sumatriptan and UK-14,304 on capsaicin-induced relaxation of guinea-pig isolated basilar artery.
1. The objectives of this study were to assess the effects of sensory neuropeptide antagonists and presynaptically acting receptor agonists on capsaicin-induced relaxations of guinea-pig isolated basilar artery (GPBA). 2. Capsaicin, human alpha-calcitonin gene-related peptide (CGRP) and substance P (SP) caused concentration-related relaxations of GPBA which had been pre-contracted with prostaglandin F2 alpha (PGF2 alpha). Responses to capsaicin were not modified by the peptidase inhibitors, phosphoramidon (1 microM) and bestatin (100 microM). 3. The relaxant responses to capsaicin were blocked in a selective manner by ruthenium red (3 microM) and by the CGRP antagonist, CGRP8-37 (1 microM). CGRP8-37 also selectively inhibited the relaxant effects of CGRP. 4. The selective NK1 receptor antagonist, GR82334 (10 microM), inhibited SP-induced relaxations but had little effect on capsaicin-induced relaxations. 5. The 5-HT1 receptor agonist, sumatriptan, produced small contractions of GPBA under conditions of resting tone. In the presence of PGF2 alpha, sumatriptan had no further contractile effect. Sumatriptan (0.3 and 3 microM) did not modify capsaicin-induced relaxations of GPBA. 6. The alpha 2-adrenoceptor agonist, UK-14,304 (0.1 microM), had no effect on basal or PGF2 alpha-induced tone. UK-14,304 did not modify capsaicin-induced relaxations. 7. These results suggest that capsaicin causes relaxation of GPBA via a release of CGRP. This process is amenable to blockade by CGRP8-37 and ruthenium red, but not to modulation by either sumatriptan or UK-14,304.


Pimozide modulates the luteinizing hormone-releasing hormone effect on gonadotrophin release in the African catfish, Clarias lazera.
In the African catfish the effect of (i) the dopamine antagonist pimozide (PIM), (ii) a luteinizing hormone-releasing hormone analog (LH-RHa), and (iii) a combination of these substances on gonadotrophin (GTH) release and on ovulation was investigated. PIM alone increased plasma GTH levels in juvenile catfish but was ineffective in mature animals. LH-RHa increased plasma GTH levels in both juvenile and mature catfish and within 12 hr after the injection a high rate of ovulation (80%) was observed. PIM potentiated the LH-RHa effect on GTH release and ovulation. It was concluded that dopamine does not effect the GTH release directly, but modulates the effect of endogenous and exogenous gonadotrophin-releasing hormone.


Bioequivalence of 20-mg once-daily tamoxifen relative to 10-mg twice-daily tamoxifen regimens for breast cancer.
We studied the bioequivalence of a new once-daily regimen of tamoxifen citrate relative to the standard twice-daily regimen of tamoxifen citrate, an established antiestrogenic treatment for breast cancer. Of 30 women with breast cancer, 27 completed this open, two-period, crossover randomized trial. During one 3-month period, patients took one standard 10-mg tamoxifen tablet twice daily; during the preceding or following 3-month period, patients took one of the new 20-mg tablets once daily. Pharmacokinetic profiles and safety parameters were assessed at the end of each 3-month treatment period. Overall, measured concentrations of tamoxifen and its principal active metabolite, N-desmethyltamoxifen, remained relatively constant over the 24-hour sampling periods at the end of each treatment sequence. For both compounds, the percentage differences of the geometric means for all pharmacokinetic parameters indicated bioequivalence of the once-daily regimen of tamoxifen relative to the standard twice-daily regimen. Both treatment sequences were well tolerated; reported adverse events occurred at similar frequencies with the two treatment regimens. The 20-mg tamoxifen tablet taken once daily was bioequivalent to the 10-mg tamoxifen tablet taken twice daily, with no difference in relative risk. The once-daily treatment is a simpler regimen and may facilitate compliance, which may enhance therapeutic outcomes during long-term treatment of breast cancer.


Percutaneous transhepatic catheterization of the portal vein for the study of portal hemodynamics and shunts. A preliminary report.
A technique for catheterizing the portal vein transhepatically, based on our method for percutaneous transhepatic cholangiography, is described. Using this technique, quantitation of the intrahepatic shunt and extrahepatic shunt from the splenoportal axis is possible. It involves injection of 99mTc-macroaggregated albumin into the splenic vein at the splenic hilum and 131I-macroaggregated albumin into the portal trunk, followed by differential counting over predetermined areas of the liver and lungs. Catheterization was successful in 20 of 30 patients in whom it was attempted. The intrahepatic shunt indices varied from 1.0 to 78.4% and the extrahepatic shunt indices ranged from 0 to 49.9%. These values appeared to correlate closely with the size of collaterals opacified by portography.


Aflatoxin B1-induced early developmental hepatotoxicity in larvae zebrafish.
Aflatoxin B1 (AFB1) is a ubiquitous mycotoxin that causes oxidative damage in various organs. At present, the research studies on AFB1 are primarily focused on its effects on the terrestrial environment and animals. However, its toxicity mechanism in aquatic environments and aquatic animals has not been largely explored. Thus, in this study, zebrafish was used as a model to study the toxicity mechanism of AFB1 on the liver of developing larvae. The results showed that AFB1 exposure inhibited liver development and promoted fat accumulation in the liver. Transcriptome sequencing analysis showed that AFB1 affected liver redox metabolism and oxidoreductase activity. KEGG analysis showed that AFB1 inhibited the expression of gsto1, gpx4a, mgst3a, and idh1 in the glutathione metabolizing enzyme gene pathway, resulting in hepatic oxidative stress. At the same time, AFB1 also inhibited the expression of acox1, acsl1b, pparα, fabp2, and cpt1 genes in peroxidase and PPAR metabolic pathways, inducing hepatic steatosis and lipid droplet accumulation. Antioxidant N-Acetyl-l-cysteine (NAC) preconditioning up-regulated gsto1, gpx4a and idh1 genes, and improved the AFB1-induced lipid droplet accumulation in the liver. In summary, AFB1 induced hepatic oxidative stress and steatosis, resulting in abnormal liver fat metabolism and accumulation of cellular lipid droplets. NAC could be used as a potential preventative drug to improve AFB1-induced fat accumulation.


Knowledge Domain and Emerging Trends of Glucagon-Like Peptide 1 Receptor Agonists in Cardiovascular Research: A Bibliometric Analysis.
Patients with type 2 diabetes (T2DM) are more likely to have cardiovascular disease (CVD). Glucose-lowering drugs with cardiovascular benefits represented by Glucagon-like peptide 1 receptor agonists (GLP1RAs) were discovered and gained more and more attention. Data from 1985 to the 2021 were downloaded in the Web of Science Core Collection (WoSCC) database. CiteSpaceV was used for bibliometric analysis to find research hotspots and frontiers. The 2088 papers were published by 74 countries (regions), 876 institutions, and 2203 authors. The annual publications increased over time from 2005 to 2020. DIABETES OBESITY METABOLISM published the most papers. The USA and China were the top 2 productive nations. The leading institution was the University of Copenhagen, and the most productive researcher was John B Buse. The most cited paper is "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes" (by Marso SP, 2016). The research hotspots include the effects of GLP1RA on cardiovascular outcomes, efficacy, complicated metabolic abnormalities, protective mechanisms, and other novel anti-diabetic drugs for cardiovascular protection. Research frontiers include cardiovascular studies on semaglutide, as well as the most prominent research approach in the field-placebo-controlled trial. Numerous countries, institutions, and authors have focused on GLP1RA in cardiovascular research and a great deal of literature has been published. Five research hotspots and two frontiers illustrate the current status and emerging trends of GLP1RA in cardiovascular research. The cardiovascular effects and clinical efficacy of GLP1RA are a current hot topic that is rapidly evolving and of high research value.


Information needs in patients with bladder cancer undergoing radical cystectomy - A qualitative review with thematic synthesis.
Worldwide, bladder cancer is the eleventh most common cancer. Self-care is significant after surgery and optimal information needs to be individualized. This will help the patient to understand and become involved in their own care. This study investigated experiences of information needs in patients with bladder cancer undergoing radical cystectomy. A qualitative review study with a thematic synthesis according to the PRISMA Statement Guidelines was performed. Thirteen peer-reviewed original articles were included. This review highlighted that patient experienced unmet information needs about postoperative care and self-care. Patients also experienced receiving too much information in a limited time. This led to difficulties in understanding and processing the information. Patients also experienced limited information about sexual and psychological support and requested more information about physical activity. Information is essential but needs to be adapted and based on person-centred care principles related to the patients' needs and wishes. Unmet needs impact patients' lives and are associated with misunderstandings and insecurity, which need to be considered in cancer nursing. The review was not registered.


Diffusion tensor imaging changes in patients with glioma-associated seizures.
Structural white matter changes associated with certain epilepsy subtypes have been demonstrated using diffusion tensor imaging (DTI). This observational study aims to identify potential water diffusion abnormalities in glioma patients with associated seizures. Two cohorts from two centers were analyzed independently: (A) Prospectively recruited patients diagnosed with glioma who received preoperative DTI to measure mean diffusivity (MD) and fractional anisotropy (FA) in regions-of-interest (ROIs) including the marginal tumor zone (TU), adjacent peritumoral white matter as well as distant ipsilateral and contralateral white matter and cortex. Data were compared between patients with and without seizures and tested for statistical significance. (B) A retrospective cohort using an alternative technical approach sampling ROIs in contrast enhancement, necrosis, non-enhancing tumor, marginal non-enhancing tumor zone, peritumoral tissue, edema and non-tumorous tissue. (A) The prospective study cohort consisted of 23 patients with 12 (52.2%) presenting with a history of seizures. There were no significant seizure-associated differences in MD or FA for non-tumor white matter or cortical areas. MD-TU was significantly lower in patients with seizures (p = 0.005). (B) In the retrospective cohort consisting of 46 patients with a seizure incidence of 50.0%, significantly decreased normalized values of MD were observed for non-enhancing tumor regions of non-glioblastoma multiforme (GBM) cases in patients with seizures (p = 0.022). DTI analyses in glioma patients demonstrated seizure-associated diffusion restrictions in certain tumor-related areas. No other structural abnormalities in adjacent or distant white matter or cortical regions were detected.


When No One's The Expert: A Preliminary Study of Social Workers' Perspectives on Shared Loss in Counseling During COVID-19.
In this preliminary study, social workers' experiences of adjustment and loss during the coronavirus disease (COVID-19) pandemic were explored as they, along with their clients, coped with the resulting emotional and psychological impacts. As death and illness rates increased alarmingly, masters-level social work students' discourses and feedback in a course on grief and loss revealed a knowledge gap surrounding counseling in face of shared loss that led to a pilot study. Subsequently, a qualitative research study (n = 7) of video self-reports from clinical social workers was conducted to further explore their losses and their consequent professional impact. They responded to the question, "What losses have you felt in this pandemic that have impacted you professionally?" Participants listed multiple losses related to work (e.g., loss of professional therapeutic space, loss of the work/life divide) and recognized the challenges to maintaining a personal sense of well-being. In consideration of the pandemic's impact when counseling others, participants identified the following themes: greater emphasis on one's own well-being, greater focus on maintaining strong therapeutic rapport, the value of creativity in the new therapeutic space, and a continual assessment of dynamic shifts. For society to process-which means, largely, to grieve-the losses related to COVID-19 and adjust to the world as is, there is a need for counselors to do so as well. This paper explains how some counselors have experienced loss through their work and coped with it; thus, they have been able to support their clients through the pandemic.


New parameters for childhood ventilator associated pneumonia diagnosis.
Our aim is to determine whether the presence of soluble triggering receptor expressed on myeloid cells-1 (s-TREM-1) of bronchoalveolar lavage fluid (BALF), serum procalcitonin levels (PCT), and Clinical Pulmonary Infection Score (CPIS) have diagnostic value in children with VAP. All children followed in pediatric intensive care unit (PICU) who were mechanically ventilated at least for 48 hr between January 2014 and December 2015 were enrolled into our study. BALF sample was obtained via non-bronchoscopic method from the children with VAP suspicion (case group) and s-TREM-1 levels were measured. Furthermore we calculated CPIS and measured serum PCT levels. Same procedures were applied to the control group who were admitted to PICU without infectious problems and who were not under antimicrobial therapy. First we compared the case group with the control group and then we compared the quantitative culture confirmed and non-confirmed VAP cases among themselves. Case group (n:58) had significant higher PCT and s-TREM-1 levels compared to control group (n:58). The VAP confirmed cases had higher s-TREM-1, PCT ve CPIS levels compared to non-confirmed VAP cases. s-TREM-1, PCT ve CPIS variables were found to be independent risk factors for VAP. The cutoff values for s-TREM-1, CPIS, and PCT, are 281 pg/ml, 6, and 1.9 ng/ml, respectively. The patients whose s-TREM-1, CPIS, and PCT values above the cutoff levels were found to have higher cumulative VAP rate. s-TREM-1 of BALF, serum PCT levels, and CPIS are useful predictors for ventilator-associated pneumonia diagnosis in children. Pediatr Pulmonol. 2017;52:119-128. © 2016 Wiley Periodicals, Inc.


Increased Numbers of Enteric Glial Cells in the Peyer's Patches and Enhanced Intestinal Permeability by Glial Cell Mediators in Patients with Ileal Crohn's Disease.
Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohn's disease (CD) is elusive. Microscopic erosions over the ileal Peyer's patches are early signs of CD. The aim of this work was to assess the localization of EGC in the follicle and interfollicular region of the Peyer's patches and in the lamina propria and study the effects of EGC mediators on barrier function in CD patients and non-inflammatory bowel disease (non-IBD) controls. EGC markers, glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β) were quantified by immunofluorescence and Western blotting. Both markers showed significantly more EGC in the Peyer's patches and lamina propria of CD patients compared to the non-IBD controls. In CD patients there were significantly more EGC in Peyer's patches compared to lamina propria, while the opposite pattern was seen in controls. Barrier function studies using Ussing chambers showed increased paracellular permeability by EGC mediators in CD patients, whereas permeability decreased by the mediators in controls. We show the accumulation of EGC in Peyer's patches of CD patients. Moreover, EGC mediators induced barrier dysfunction in CD patients. Thus, EGC might have harmful impacts on ongoing inflammation and contribute to the pathophysiology of the disease.


Platypnea-orthodeoxia associated with a fenestrated atrial septal aneurysm: case report.
Platypnea-orthodeoxia describes the condition of combined dyspnea and hypoxia respectively, whilst in the upright position, which improves in the recumbent position. We present a case of platypnea-orthodeoxia due to a fenestrated atrial septal defect associated with an atrial septal aneurysm. Due to the fenestrated nature of the atrial septal defect, surgical rather than percutaneous correction was performed. A high index of suspicion is required to diagnose the syndrome of platypnea-orthodeoxia. Careful echocardiographic evaluation is required to identify the syndrome, and to determine suitability for percutaneous repair.


LncRNA-MALAT1 promotes osteogenic differentiation through regulating ATF4 by sponging miR-214: Implication of steroid-induced avascular necrosis of the femoral head.
To study roles oflncRNA-MALAT1 and miR-214 in steroid-induced avascular necrosis of the femoral head (SANFH). MALAT1, miR-214 andosteogenic-relatedgenes(Runx2, ALP, andOCN)expressions were determined in SANFH tissue samples and human bone marrow stromal cells (BMSC) by RT-qPCR. BMSCs were verifiedbyflowcytometry. The ATF4 level was determined by western blotting and RT-qPCR. Osteogenesis inducedbyosteogenic medium (OM) in BMSCs and dexamethasone (DEX) was used to inhibit osteogenesis. The alkaline phosphatase (ALP) activity was measured and ALP staining and alizarin red staining were conducted for evaluation of osteogenic differentiation. MTT assay was used for cell proliferation. The dual luciferase reporter assay was used to confirm binding between MALAT1 and miR-214, as well as miR-214 and ATF4. MALAT1 was down-regulated and miR-214 was up-regulated in SANFH tissues. DEX inhibited osteogenic differentiation of BMSC in a dose-dependent manner, leading to decreased MALAT1, increased miR-214, as well as reduced ALP activity and decreased expression of RUNX2, ALP and OCN. Either overexpression of MALAT1 or inhibition of miR-214 improved DEX-induced inhibition of BMSC osteogenic differentiation. The overexpression of miR-214 reversed the effects by MALAT1. MALAT1 directly sponged miR-214 and miR-214 directly targeted ATF4. MALAT1 was down-regulated, while miR-214 was elevated in SANFH tissues. MALAT1 promoted osteogenesis differentiation by sponging miR-214 to upregulate ATF4.


Macrophage Inhibition Factor-Mediated CD74 Signal Modulate Inflammation and Matrix Metabolism in the Degenerated Cartilage Endplate Chondrocytes by Activating Extracellular Signal Regulated Kinase 1/2.
The macrophage inhibition factor (MIF)-mediated CD74 dependent extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were associated with inflammatory activity and matrix metabolism in human degenerated cartilage endplate (CEP). Anabolic/catabolic factors in pathogenesis of CEP degeneration were evaluated. To study the effect of MIF-mediated CD74 dependent ERK1/2 activation on the CEP degeneration. MIF-CD74 signal is closely related to the CEP degeneration by inducing the secretion of inflammatory cytokines. ERK1/2-mediated inflammatory pathway also plays a crucial role in the intervertebral disc degeneration. The role of the ERK1/2 pathway in CEP chondrocytes response to MIF-CD74 signal has, however, not been fully elucidated. Chondrocytes were exposed to MIF, with or without ERK1/2 inhibition; CD74 interfered chondrocytes were also exposed to MIF, with or without ERK inhibition. mRNAs were isolated for real-time polymerase chain reaction measurement of gene expression. Western blotting was carried out to analyze the protein expression. ERK1/2 expression was significantly increased by MIF. MIF modulates metabolism in CEP chondrocytes and decreased by its inhibitor PD98059. ERK1/2 expression was significantly decreased by CD74siRNA. Inflammatory cytokines expression was significantly increased by MIF-induced ERK1/2 activation and significantly suppressed by PD98059. On the contrary, matrix expression was significantly decreased by MIF-induced ERK1/2 activation and reversed by PD98059. CD74siRNA decreased the CD74 expression in chondrocytes. Inflammatory cytokines and matrix expression were not induced by MIF in CD74 interfered chondrocytes. These results show that MIF-CD74 signal elicits an imbalance between anabolic and catabolic metabolism in CEP chondrocytes via ERK signal pathway. ERK inhibition could exert therapeutic effect against the harmful effects of MIF-CD74 signal in CEP degeneration. N/A.


Zoledronic acid regulates the synthesis and secretion of IL-1β through Histone methylation in macrophages.
Long-term administration of nitrogen-containing bisphosphonates increases the risk of detrimental side effects, such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). BRONJ development is associated with inflammation, but its pathophysiology remains unknown. Here, we examined whether histone methylation is responsible for zoledronic acid (Zol)-induced inflammatory responses. We found that Kdm6a and Kdm6b markedly increased interleukin 1β expression and Gasdermin D cleavage, which are both activated by Caspase 1, in macrophages. Inhibitors of Kdm6a and Kdm6b robustly abolished Zol-enhanced interleukin 1β synthesis and secretion from macrophages. When Kdm6a and Kdm6b were pharmacologically inhibited in vivo, poor healing of the alveolar socket and inflammatory responses were ameliorated in Zol-treated mice. Taken together, we showed the pathologic role of Kdm6a and Kdm6b in Zol-promoted inflammatory responses and demonstrated that Kdm6a and Kdm6b are potential therapeutic targets for the treatment of BRONJ.


Bioactive and mechanically stable hydroxyapatite patterning for rapid endothelialization of artificial vascular graft.
Polymeric vascular grafts have been widely used in the vascular regeneration field because of their ease of application. However, synthetic polymer grafts have the severe problem of low biocompatibility, which may cause delayed endothelialization and hyperplasia. In this study, we fabricated a linear hydroxyapatite (HA) pattern on a silicon wafer and then transferred the pattern to a poly(L-lactic)-acid (PLLA) film for use as a tubular vascular graft. The HA pattern with its characteristic needle-like shape was successfully embedded into the PLLA. The HA-patterned PLLA film exhibited superior mechanical stability compared with that of a HA-coated PLLA film under bending, elongation, and in vitro circulation conditions, suggesting its suitability for use as a tubular vascular graft. In addition, the HA pattern guided rapid endothelialization by promoting proliferation of endothelial cells and their migration along the pattern. The hemocompatibility of the HA-patterned PLLA was also confirmed, with substantially fewer platelets adhered on its surface. Overall, in addition to good mechanical stability, the HA-patterned PLLA exhibited enhanced biocompatibility and hemocompatibility compared with pure PLLA.


The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application.
Better understanding of biases related to selective prescribing of, and adherence to, preventive treatments has led to improvements in the design and analysis of pharmacoepidemiologic studies. One influential development has been the "active comparator, new user" study design, which seeks to emulate the design of a head-to-head randomized controlled trial. In this review, we first discuss biases that may affect pharmacoepidemiologic studies and describe their direction and magnitude in a variety of settings. We then present the historical foundations of the active comparator, new user study design and explain how this design conceptually mitigates biases leading to a paradigm shift in pharmacoepidemiology. We offer practical guidance on the implementation of the study design using administrative databases. Finally, we provide an empirical example in which the active comparator, new user study design addresses biases that have previously impeded pharmacoepidemiologic studies.


Structural determinants in the stability of the serpin/proteinase complex.
Serpins inhibit serine proteinases through formation of stable 1:1 complexes. In this study we have evaluated the effects of PAI-1 neutralizing antibodies (MA) on the stability of PAI-1/proteinase complexes, partially destabilized through prolongation of the reactive center loop. MA-8H9D4, reacting with residues Arg(300), Gln(303), and Asp(305), had no effect on the stability. In contrast, MA-33H1F7 and MA-55F4C12, reacting with alpha-helix F and the turn connecting hF with s3A, affected significantly and proteinase-dependently formed PAI-1/proteinase complexes. That is, MA-33H1F7 increased the stability of both PAI-1/t-PA and u-PA complexes (7- and 3-fold, respectively) whereas MA-55F4C12 stabilized PAI-1/t-PA complexes (3-fold) but destabilized PAI-1/u-PA complexes (2-fold). It is concluded that interference with the docking site of the cognate proteinase in the preformed serpin/proteinase complex may affect the intrinsic stability. We hypothesize that this is the consequence of a decreased or increased torsion of the RCL on the catalytic triad in the proteinase.


Mitigating the BFL1-mediated antiapoptotic pathway in diffuse large B cell lymphoma by inhibiting HDACs.
Endogenous BFL1 expression renders diffuse large B-cell lymphoma (DLBCL) cells insensitive to B-cell lymphoma 2 (BCL2) and/or MCL1 inhibitors. Considering the difficulties in developing a direct BFL1 inhibitor, we intended to inhibit histone deacetylase (HDAC) to mitigate the biological role of BFL1 by modulating WT1 and NOXA. Cells expressing high BFL1 exhibited enhanced sensitivity to pan-HDAC inhibitor compared to low BFL1 expressing cells, mainly attributable to the difference in the amount of apoptosis. HDAC inhibitors decreased BFL1 and WT1 expressions while increasing NOXA levels. The BFL1 knockdown experiment demonstrated that HDAC inhibitor's sensitivity depends on the BFL1 expression in DLBCL cells. Furthermore, we found that the specific HDAC class was expected to play a critical role in BFL1 inhibition by comparing the effects of several HDAC inhibitors. Thus, our study provides a rationale for using HDAC inhibitors to induce apoptosis in DLBCL patients using BFL1 as a predictive biomarker.


The Psychosocial Burden of HCV Infection and the Impact of Antiviral Therapy on the Quality of Life in Liver and Kidney Transplant Recipients: A Pilot Study.
Therapy with direct-acting antivirals (DAA) for HCV is safe and effective in the liver (LT) and kidney transplant (KT) recipients; however, data on the quality of life (QoL) of patients are scanty. This pilot study is aimed at prospectively evaluating the QoL in LT and KT recipients before and after DAA treatment. We prospectively enrolled 17 LT and 11 KT recipients with HCV infection starting a sofosbuvir-based antiviral therapy for 12 weeks. All participants before (T0), 12 (T12), and 24 (T24) weeks after the end of the therapy completed the Short Form Health Survey (SF-36) questionnaire, the Zung Self-rating Depression Scale, and State-Trait Anxiety Inventory (STAI-Y1-Y2). At T0, LT and KT patients were similar for gender, age, BMI, smoking habits, marital status, mean liver stiffness values at Fibroscan, and HCV genotype distribution (p > 0.05). There were no significant differences between the 2 groups in STAI-Y1, STAI-Y2, Zung, and SF-36 scores (p > 0.05). At T12, all the participants showed a sustained virological response (SVR). All items of the SF-36 questionnaire improved from the pretreatment to posttreatment period within the LT group, and the 4 domains role-physical, bodily pain, social function, role-emotional, and mental health reached statistical significance (p < 0.05 in all cases). On the contrary, in KT patients, there was no significant improvement in SF-36 mean scores compared to at baseline at T12 and T24. This pilot study suggested that DAA therapy is associated with a significant improvement of the QoL only in LT recipients. Probably, KT recipients did not consider HCV a "central player" in the course of their disease, and HCV eradication did not significantly impact on their QoL.


Readability of online dengue materials: The need for accessible information as part of infectious disease prevention and control efforts.
Dengue is the fastest spreading viral infection. A number of epidemics have occurred in subtropical and tropical regions of the United States. A future expansion and intensification of dengue has been predicted, partly due to changing environmental conditions. In the absence of treatment, prevention and control are vital to addressing this vector-borne disease. Health education and community engagement are a key part of such efforts. Given that the majority of Americans search for health information online, ensuring the readability of web-based dengue information is an important consideration for health officials. To date, there is a dearth of information on this topic. To address this gap, "Dengue fever" was searched using Google Chrome to generate a sample of 100 websites. Using Readable.io, the readability of these 100 sites was then determined using five different tests. The data were analyzed using SPSS. The results indicate that the vast majority of online materials on dengue are written at a level far beyond what is recommended. Three of the five tests did not find any of the sampled sites to be appropriate in terms of readability. In general, the websites analyzed tended to be written at a level beyond the 10th grade. These findings have important implications for future dengue outbreaks in the United States.


Right ventricular function early after total or standard orthotopic heart transplantation.
Right ventricular failure after orthotopic heart transplantation (OHT) is classically related to preoperative pulmonary hypertension. However, the role of the enlarged atria in right ventricular dysfunction after OHT remains unclear. For that purpose, the right ventricular function in the first 2 days after OHT was compared in two groups of transplant recipients: 11 patients who underwent standard OHT (group I) and 9 patients who underwent total OHT, which consisted of total excision of both the left and right atria and OHT of an intact donor heart with its atria as well as its ventricle (group II). Right ventricular ejection fraction, cardiac index, and right-sided pressures were recorded at baseline and 4, 8, 12, 24, and 48 hours after OHT using a Swan-Ganz catheter with a rapid-response thermistor. Right ventricular function parameters did not differ between groups; they were characterized by a decrease in right ventricular ejection fraction and an increase in right ventricular end-diastolic volume index whereas cardiac index and right-sided pressures remained normal or slightly increased. Ischemic time (177 +/- 41 minutes in group I versus 178 +/- 39 minutes in group II) and preoperative pulmonary vascular resistance (1.9 +/- 0.7 Wood units in group I versus 3.0 +/- 1.5 Wood units in group II) were not different between groups. These results suggest that the anatomic and physiologic advantages offered by the modified technique of OHT had no clinical relevance in this group of patients with low preoperative pulmonary vascular resistances when compared with a group of patients who underwent transplantation with the standard technique.(ABSTRACT TRUNCATED AT 250 WORDS)


Establishment of a luciferase-based method for measuring cancer cell adhesion and proliferation.
Methods measuring cell proliferation and adhesion are widely used but each hold limitations. We, therefore, introduce novel methods for measuring cell proliferation and adhesion based on CRISPR-modified cancer cell lines secreting luciferase to the growth media. Using CRISPR genome editing, we generated stable luciferase-secreting LS174T, HCT 116, Caco-2, and PANC-1 cell lines. The modified cells were seeded, and luciferase activity was measured in the media and compared to Coulter counter cell counts and iCELLigence impedance assay to evaluate the value of the secreted luciferase activities as a measurement for adhesion and proliferation. Our results demonstrate that luciferase secreted into the media can be used quantifying cell proliferation and adhesion. The adhesion luciferase assay and the iCELLigence impedance assay showed similar results with increased significant difference observed in the luciferase assays. The luciferase proliferation assay showed increased growth following increased serum concentrations in all cell lines vs. only two cell lines in the iCELLigence impedance assay. Our results show that the luciferase adhesion and proliferation assays are reliable methods for measuring adhesion and proliferation. The luciferase assays have advantages over existing assays as they are highly sensitive, easy to perform, non-invasive and suitable as high-throughput measurements.


Cytobrush in evaluation of cervical dysplasia. Is cervical curettage necessary?
203 patients suspected of having dysplasia were evaluated by colposcopy, cytologic smear including cytobrush, endocervical curettage, biopsy and conization. The results obtained on the basis of the final cone suggested that directed biopsies and cytological smear by spatula and cytobrush more accurately define the dysplastic lesion than do biopsies and endocervical curettage. Conization seemed necessary for the evaluation of the cervical lesion in patients revealing non-classified dysplasia at successive examinations.


Malignant progression of angioimmunoblastic lymphadenopathy.
In a 79-year-old woman, the progression of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) to malignant lymphoma was observed within one year after diagnosis. Three biopsy specimens from lymph nodes and one tonsil, obtained at intervals of several months, showed an increasing destruction of the tissue architecture and the development of histological criteria for a lymphoid neoplasm, which at autopsy was confirmed as a malignant non-Hodgkin's lymphoma. The demonstration of a chromosomally abnormal clone in lymph node derived and the laboratory findings were in agreement with the histological changes and the sequential clinical deterioation. Initially, a symptom-free interval of eight months was achieved with prednisone therapy. However, this treatment failed after the malignant transformation had become evident.


The influence of sidechains on the calculated dimensions of three related bacterial polysaccharides.
The effect of van der Waals interactions between sidechain and backbone on the shape of three bacterial polysaccharides in solution has been investigated. The three polymers, namely, gellan, welan, and rhamsan, share the same four-sugar backbone repeating-unit. Gellan is unbranched, whereas welan and rhamsan display comblike branching. Consequently, the effect of chain branching on backbone conformation may be investigated. Van der Waals repulsive interactions of sidechain and backbone serve to limit, somewhat, the range of conformational freedom of the welan backbone in comparison to that of gellan. Attractive side-chain-backbone interactions, which may be as significant as 2-3 kcal/mol, predominate over much of the accessible conformational space of the welan backbone. Despite the strength of these interactions, the unperturbed shape of welan in solution is calculated to be very similar to that of the unbranched gellan. Attractive sidechain-backbone interactions in rhamsan have a modest influence on the conformational characteristics of the rhamsan backbone. The calculated, unperturbed conformation in solution is slightly more extended than that of gellan and welan, but the fundamental shape of the chain is changed only slightly. Significant differences in the physical properties of these polymers seem not to arise from differences in their random-coil conformations provoked by van der Waals interactions of sidechain and backbone. Other contributions to the sidechain-backbone interaction, e.g., hydrogen bonding, could be involved; interchain interactions are also likely to be important.


K2CO3-promoted synthesis of amides from 1-aryl-2,2,2-trifluoroethanones and amines under mild conditions.
A base-promoted amidation of 1-aryl-2,2,2-trifluoroethanones with amines via Haller-Bauer reaction has been developed. In this reaction, the direct transformation of 1-aryl-2,2,2-trifluoroethanones into amides via C(O)-C bond cleavage occurs without the use of any stoichiometric chemical oxidants or transition-metal catalysts. A series of primary and secondary amines are shown to be compatible with this transformation, and several pharmaceutical molecules were synthesized.


Uncapping of viral messenger RNA by phosphodiesterase of fibroblast plasma membranes.
Isolated plasma membranes from mouse fibroblast lines 3T3 and its tranformant SV-3T3 contain a phosphodiesterase (oligonucleotidase, E.C. 22.214.171.124; nucleotide pyrophosphatase, E.C. 126.96.36.199) that splits capped and methylated messenger RNA obtained from both reovirus and vesicular stomatitis virus. The isolated membranes are free of demonstrable ribonuclease activity and split the mRNA to produce 7-methyl guanosine diphosphate as a product. With ATP as substrate for the phosphodiesterase enzyme, the product is AMP. Synthetic caps, AMP, ADP and ATP, but not cyclic AMP, can compete with the substrate p-nitrophenyl thymidilic acid. A possible regulatory role on messenger translation is proposed.


Use of peer role models to increase Pap smear and mammogram screening in Mexican-American and black women.
We evaluated the use of a community-based intervention model to increase Pap smear and mammogram screening in minority women. The community programs were based on the A Su Salud (To Your Health) model, which includes the presentation of positive role models in the media and positive social reinforcement by community volunteers. Mexican-American women 40-70 years of age in Corpus Christi, Texas, and black women 40-70 years of age in Galveston, Texas, were targeted. Role models from the target community told their personal stories about cancer screening through local media (television, radio, and newspapers). Volunteers reinforced media messages among the target audience by distributing newsletters. Preintervention and postintervention cross-sectional surveys among the target group measured relative increases in knowledge, attitude, and practice. Pap smear use (past two years) was not substantially improved. Mammogram use (past two years) increased 57% among Mexican-American women (prevalence rate ratio [PRR] = 1.57; 90% confidence interval [CI] = 1.19, 2.08) and 30% among black women (PRR = 1.30; 90% CI = 1.04, 1.63). We demonstrated the feasibility of implementing a peer role model intervention at the local health department level. The improvement in mammogram use among high-risk women is encouraging, but further controlled research is needed to test the effectiveness and cost-efficiency of this approach.


Occurrence, distribution and health risk from polycyclic aromatic compounds (PAHs, oxygenated-PAHs and azaarenes) in street dust from a major West African Metropolis.
Scientific evidence suggests that the burden of disease on urban residents of sub-Saharan African Countries is increasing, partly as a result of exposure to elevated concentrations of toxic environmental chemicals. However, characterization of the levels, composition pattern and sources of polycyclic aromatic compounds (PACs) in environmental samples from African cities is still lacking. This study measured the PAHs, oxygenated-PAHs (OPAHs) and azaarene (AZAs) content of street dusts collected from Kumasi, Ghana (a major metropolis located in the tropical forest zone of West Africa). The ∑Alkyl+parent-PAHs, ∑OPAHs and ∑AZAs concentration in street dust averaged 2570 ng g(-1) (range: 181-7600 ng g(-1)), 833 ng g(-1) (57-4200 ng g(-1)) and 73 ng g(-1) (3.3-240 ng g(-1)), respectively. The concentrations of ∑Alkyl+parent-PAHs were strongly correlated (n=25) with ∑OPAHs (r=0.96, p<0.01) and ∑AZAs (r=0.94, p<0.01). The ∑OPAHs concentrations were also strongly correlated with ∑AZAs (r=0.91, p<0.01). Concentrations of individual PAHs in these street dusts were enriched at between 12 and 836 compared to their average concentrations in background soils from same city, demonstrating the high influence of traffic emissions. Several individual OPAHs and AZAs had higher concentrations than their related and often monitored parent-PAHs. The estimated incremental lifetime cancer risks due to the parent-PAHs in street dusts was >10(-6) indicating high risk of contracting cancer from exposure to street dust from Kumasi. The contribution of OPAHs, AZAs, and alkyl-PAHs in street dust to cancer risk could not be quantified because of lack of toxicity equivalency factors for these compounds; however this could be significant because of their high concentration and known higher toxicity of some polar PACs and alkyl-PAHs than their related parent-PAHs.


Long-range gene regulation in hormone-dependent cancer.
The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment.


Submicroscopic chromosome imbalance in patients with developmental delay and/or dysmorphism referred specifically for Fragile X testing and karyotype analysis.
Microdeletion syndromes are generally identified because they usually give rise to specific phenotypic features; many of these deletions are mediated by duplicons or LCRs. The phenotypes associated with subtelomeric deletions are also becoming recognised. However, reciprocal duplication events at these loci are less easily recognised and identified, as they may give rise to milder phenotypic features, and the individuals carrying them may not therefore be referred for appropriate testing. 403 patients with developmental delay and/or dysmorphism, referred to our Genetics Centre for karyotyping and Fragile X expansion testing, were assessed for chromosome imbalance by Multiplex Ligation-dependent Probe Amplification (MLPA). Two MLPA kits were used, one containing probes for the subtelomere regions, and one containing probes for common microdeletion loci. 321 patients were tested with both kits, 75 with the subtelomere kit alone, and 7 with the microdeletion kit alone. 32 patients had abnormal results; the overall abnormality detection rate was 2.5% for karyotype analysis and 7.2% for MLPA testing; 5.5% of subtelomere tests and 2.1% of microdeletion tests gave abnormal results. Of the abnormal MLPA results, 5 were in cases with cytogenetically visible abnormalities; of the remaining, submicroscopic, changes, 3 results were established as de novo and 8 were inherited; parental samples were not available for the remaining cases. None of the patients was found to have a Fragile X expansion. Karyotype analysis in combination with MLPA assays for subtelomeres and microdeletion loci may be recommended for this patient group.


Effect of aqueous extract from Nigella sativa L. on guinea pig isolated heart.
A potent inhibitory effect of aqueous extract from N. sativa on calcium channel of guinea pig heart was found comparable and even greater than that of diltazem. The results may also indicate an opening effect for the plant on potassium channel of isolated heart.


Benefits of home-based multidisciplinary exercise and supportive care in inoperable non-small cell lung cancer - protocol for a phase II randomised controlled trial.
Lung cancer is one of the most commonly diagnosed cancers, and is a leading cause of cancer mortality world-wide. Due to lack of early specific symptoms, the majority of patients present with advanced, inoperable disease and five-year relative survival across all stages of non-small cell lung cancer (NSCLC) is 14%. People with lung cancer also report higher levels of symptom distress than those with other forms of cancer. Several benefits for survival and patient reported outcomes are reported from physical activity and exercise in other tumour groups. We report the protocol for a study investigating the benefits of exercise, behaviour change and symptom self-management for patients with recently diagnosed, inoperable, NSCLC. This multi-site, parallel-group, assessor-blinded randomised controlled trial, powered for superiority, aims to assess functional and patient-reported outcomes of a multi-disciplinary, home-based exercise and supportive care program for people commencing treatment. Ninety-two participants are being recruited from three tertiary-care hospitals in Melbourne, Australia. Following baseline testing, participants are randomised using concealed allocation, to receive either: a) 8 weeks of home-based exercise (comprising an individualised endurance and resistance exercise program and behaviour change coaching) and nurse-delivered symptom self-management intervention or b) usual care. The primary outcome is the between-group difference in the change in functional exercise capacity (six-minute walk distance) from baseline to post-program assessment. Secondary outcomes include: objective and self-reported physical activity levels, physical activity self-efficacy, behavioural regulation of motivation to exercise and resilience, muscle strength (quadriceps and grip), health-related quality of life, anxiety and depression and symptom interference. There is a lack of evidence regarding the benefit of exercise intervention for people with NSCLC, particularly in those with inoperable disease receiving treatment. This trial will contribute to evidence currently being generated in national and international trials by implementing and evaluating a home-based program including three components not yet combined in previous research, for people with inoperable NSCLC receiving active treatment and involving longer-term follow-up of outcomes. This trial is ongoing and currently recruiting. This trial was prospectively registered on the Australian New Zealand Clinical Trials Registry ( ACTRN12614001268639 : (4/12/14).


Herniorrhaphy in the elderly. Benefits of a clinic for the treatment of external abdominal wall hernias.
Elective abdominal herniorrhaphy carries morbidity and mortality rates of 26 percent and 1.5 percent, respectively, in patients over 65 years of age. These figures climb to 55 percent and 15 percent during emergent surgery. Our purpose was to investigate if standardization of treatment could improve such results. Our program stressed centralization of care in a hernia clinic; early operation of patients at risk of incarceration; optimization of underlying systemic disorders by consultative services; operation under local anesthesia; preoperative, operative, and postoperative protocol; and continuity of care by senior personnel. Over a 4 year period, we have performed 241 abdominal herniorrhaphies in patients over 65 years of age (median age 71.5 years old) who exhibited an 84 percent incidence of significant preoperative systemic disorders. Since the inception of our program, our rate of emergent operation has decreased significantly from 7 percent to 2 percent (chi-square less than or equal to 0.05). Our rate of systemic complications after elective operation was 1.2 percent and 0 after emergent operation. These data are statistically better than those reported in the literature (chi-square less than or equal to 0.05). These results suggest that the creation of a hernia clinic significantly improves the care of herniated patients.


Thyroid hormone induce a p53-dependent DNA damage through PI3K/Akt activation in sperm.
Accumulating evidences showed that thyroid hormone was participated in the functioning of the reproductive system, and an elevated level of thyroid hormones had a negative impact on reproductive system. However, the molecular basis for this observation still remains to be fully understood. Here, we show that l-Thyroxine significantly impaired human sperm motility. The molecular basis showed that thyroxine receptor stimulation triggers Phosphatidyl Inositol 3-kinase (PI3K)/Akt signaling activation leading to the E3 ligase MDM2 phosphorylation at serine 166, which directly interacted with p53 for degradation. p53 degradation caused a p53-dependent DNA damage checkpoint or repair dysfunction, which eventually results in DNA damage accumulation in sperm. Our results highlight that inhibition of PI3K/Akt pathway or p53 degradation is important in maintaining sperm motility in a thyroxine receptor (TR)-dependent manner.


Psychiatric symptomatology among Mexican American farmworkers.
The paper presents findings from an epidemiologic field survey of 500 Mexican American farmworkers conducted in central California. The survey was intended as a health needs assessment of this population and the Health Opinion Survey was used to establish normative psychiatric symptom distributions. Analyses of the data by gender, age and income revealed that these socio-demographic variables were not important predictors of symptom levels, although the highest mean scores were reported in the 40-59 age group. Income levels were modest and fairly uniform, which contributed to the lack of mean score variation. Symptom distributions were analyzed for the variables age and sex using the HOS criteria of caseness and it was found that approx. 20% of the sample reached the criteria of caseness. A comparison of HOS mean scores with a national sample of surveys indicated that Mexican American farmworkers had symptom levels which resemble those of other low income socio-economic groups, such as southern blacks. Another analysis was conducted which reported a striking correspondence between self perception of health with psychiatric symptoms. A conclusion reached from the survey is that the Mexican American farmworkers in this sample appear to be experiencing psychiatric symptom levels which place them at extraordinary risk. Stresses associated with this group, i.e., limited social mobility, transience, poverty, discrimination and a high rate of traumatic life events were identified as possible contributors to this risk proneness.


The added value of chest imaging after neoadjuvant radiotherapy for soft tissue sarcoma of the extremities and trunk wall: A retrospective cohort study.
There is no clear evidence regarding the benefit of restaging for distant metastases after neoadjuvant radiotherapy (RTX) in patients with soft tissue sarcoma (STS) of the extremities and trunk wall. This study aimed to determine how often restaging of the chest identified metastatic disease that altered management in these patients. We performed a single-centre retrospective study from 2010 to 2020. All patients with non-metastatic STS of the extremities and trunk wall who were treated with neoadjuvant RTX and received a staging and restaging chest CT scan or X-ray for distant metastasis were included. The outcome of interest was change in treatment strategy due to restaging after neoadjuvant RTX. Within the 144 patients who were staged and treated with neoadjuvant RTX, a restaging chest CT or X-ray was performed in 134 patients (93%). A change in treatment strategy due to new findings at restaging after RTX was observed in 26 out of 134 patients (19%). In 24 patients the scheduled resection of the primary STS was cancelled at restaging (24/134, 18%), given the findings at restaging. The other two patients did receive the intended local resection, but either with palliative intent, or as a part of a previously unplanned multimodality treatment. In approximately one in five patients restaging results in a change in treatment strategy. This underlines the added value of routine restaging for distant metastases with chest CT or X-ray after neoadjuvant RTX in patients with STS.