Methodologic implications of allocating multiple-race data to single-race categories.
To illustrate methods for comparing race data collected under the 1977 Federal Office of Management and Budget (OMB) directive, known as OMB-15, with race data collected under the revised 1997 OMB standard. Secondary data from the 1993-95 National Health Interview Surveys. Multiple-race responses, available on in-house files, were analyzed. Race-specific estimates of employer-sponsored health insurance were calculated using proposed allocation methods from the OMB. Estimates were calculated overall and for three population subgroups: children, those in households below poverty, and Hispanics. Although race distributions varied between the different methods, estimates of employer-sponsored health insurance were similar. Health insurance estimates for the American Indian/Alaska Native group varied the most. Employer-sponsored health insurance estimates for American Indian/Alaska Natives from data collected under the 1977 OMB directive will not be comparable with estimates from data collected under the 1997 standard. The selection of a method to distribute to the race categories used prior to the 1997 revision will likely have little impact on estimates of employer-sponsored health insurance for other groups. Additional research is needed to determine the effects of these methods for other health service measures.


piRNA-triggered MIWI ubiquitination and removal by APC/C in late spermatogenesis.
The PIWI/PIWI-interacting RNA (piRNA) machinery has been well documented to maintain genome integrity by silencing transposons in animal germ cells. Recent studies have advanced our understanding of the biogenesis and function of this machinery; however, its metabolism has remained largely unexplored. Here, we show that murine PIWI (MIWI) is degraded through the APC/C-26S proteasome pathway and that piRNAs play an indispensable role in this process by enhancing MIWI interaction with an APC/C substrate-binding subunit. Interestingly, piRNA-triggered MIWI destruction occurs in late spermatids, which in turn leads to piRNA elimination, suggesting a feedforward mechanism for coordinated removal of the MIWI/piRNA machinery at a specific developmental stage. Importantly, the proper removal of MIWI/piRNA is essential for sperm maturation. Together, our results reveal a role for piRNAs in regulating the clearance of the MIWI/piRNA machinery via the ubiquitin-proteosome pathway and demonstrate the critical importance of proper temporal regulation of MIWI/piRNA in male germ cell development.


Correction to: Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients.
Because of a technical error, the code corresponding to the outcome for the Basir et al. cohort was mis-implemented in the original version of our article. Characteristics of the cohort are in fact the followings.


Turning clustering loops: sex determination in Caenorhabditis elegans.
The nematode Caenorhabditis elegans has two sexes: males and hermaphrodites. Hermaphrodites are essentially female animals that produce sperm and oocytes. In the past few years tremendous progress has been made towards understanding how sexual identity is controlled in the worm. These analyses have revealed that the regulatory pathway controlling sexual development is far from linear and that it contains a number of loops and branches that play crucial roles in regulating sexual development. This review summarizes our current understanding of the mechanisms that regulate sexual cell fate in C. elegans.


Total lab automation: sample stability of clinical chemistry parameters in an automated storage and retrieval module.
Automated storage and retrieval modules (SRM), as part of total lab automation (TLA) systems, offer tremendous practical and economic benefits. In contrast to manual storage systems, SRMs indicate continuous motion of samples and may leave samples prone to temperature fluctuations. This study investigates analyte stability in serum and heparin plasma within an automated storage module. The stability of 28 common biochemistry analytes was investigated using 57 freshly obtained routine serum samples and 42 lithium-heparin plasma samples. Following baseline measurement, samples were stored at 2-8 °C in the automated SRM of the Accelerator a3600 TLA and reanalyzed at fixed time points (2, 4, 8, 12, 24, 48 and 72 h) on the Abbott Architect c16000 chemistry analyzer. The concentration at each time point was expressed as %-difference to the baseline value and mean results were compared to the criteria for desirable bias derived from the biological variation database. Nine of the analytes exceeded the bias criterion within 72 h after initial measurement in either serum samples, plasma samples or both. Lithium-heparin plasma samples showed increasing values for phosphor, potassium and lactate dehydrogenase (LDH), which were only considered stable for respectively 24, 12 and 4 h, glucose was considered stable for 8 h. Electrolyte concentrations and LDH activity significantly increased in serum samples beyond 48 h. Bicarbonate should not be performed as add-on test at all. The presented data indicate that the conditions within an SRM have no clinical impact on sample stability and allow stable measurement of routine analytes within 72 h, comparable to manual storage facilities.


Rebreathing K(CO) and single breath K(CO) measured at the same mean alveolar volume reveal a physiological relationship between unequal diffusion and unequal ventilation in normal subjects.
The single breath (SB) method for determining the transfer factor for carbon monoxide is influenced by an unequal distribution of diffusion and ventilation. The rebreathing (RB) method is thought not to be influenced by these inequalities. Therefore, a comparison of the results of the two methods enables us to investigate unequal ventilation and diffusion. We have previously shown that even in normal subjects unequal ventilation influences the relation between the transfer factor as measured by the RB method and by the SB method. To investigate to what extent unequal diffusion influences the relation between the RB and SB transfer factor in normal subjects. Measurements were performed in 8 normal subjects. Differences in alveolar volume as measured by the RB and SB method were prevented from influencing the results by comparing the RB and SB transfer factor per liter of alveolar volume, i.e. the RB and SB Krogh factor, instead of the RB and SB transfer factor. The effect of the known dependence of the Krogh factor on inspired volume was prevented by measuring the SB Krogh factor at an inspired volume equal to the mean inspired volume of the RB measurement. This SB Krogh factor was compared with the RB Krogh factor calculated as the quotient of the RB transfer factor and the mean alveolar volume during the RB measurement. This RB Krogh factor was always larger than the corresponding SB Krogh factor. The difference was significant (p = 0.006). A high percentage (80%) of the variance in the quotient of the two Krogh factors, which can be considered as a parameter for unequal diffusion, was explained by the variance in the quotient of the mean RB volume and the corresponding SB volume. The latter quotient is a measure of unequal ventilation. The finding suggests a physiological relation between unequal diffusion and unequal ventilation. A plausible explanation was found in the decrease of the Krogh factor with an increasing ratio of inspired volume to residual volume for each part of the lung separately. The consequence is that in the absence of unequal ventilation the RB transfer factor is equal to the SB transfer factor measured at an inspired volume equal to the mean RB inspired volume.


Student-faculty relationships and its impact on academic outcomes.
The aim of this review of the literature is to synthesis the knowledge attained about determinants of student-faculty relationships and its impact on student outcomes. While adding to the body knowledge, the researchers discuss the importance, barriers, and facilitators to student-faculty academic relationships in nursing education. We conducted a narrative literature review using a modified version of the framework of the Population, Intervention, Comparison, and Outcome method to develop the research question for this review. That question was: What determinants of undergraduate nursing students' relationships with faculty affect those students' academic outcomes? To search and review the literature systematically, we entered the specific criteria into the EBSCOhost interface. The following databases were used for data sourcing: Cumulative Index to Nursing and Allied Health Literature Plus with Full Text; Teacher Reference Center; Education Resources Information Center; Medline; and Theses and Dissertations. We selected only full-text, peer-reviewed sources that were written in English for final inclusion. After the retrieval of 56 reports via an EBSCO host search, abstracts were reviewed and 29 were rejected based on the exclusion/inclusion criteria. The rejected reports met some or no criteria and not others; or showed little to no association with determinants of nursing student-faculty academic relationships or students' academic outcomes. An inductive method of analysis was used to review and extract emerging themes. Findings revealed four core determinants of student-faculty relationships: support, caring, diversity, and incivility. These determinants were interrelated and appeared to have an impact on student academic outcomes. Nursing institutions should be proactive to ensure that barriers such as incivility are reduced and that diversity is included and appreciated in the teaching and learning environment. Additionally, a caring and supportive climate of learning should be emphasized and enacted by nurse educators.


Mechanism of Coomassie brilliant blue G-250 binding to proteins: a hydrophobic assay for nanogram quantities of proteins.
We investigated the mechanism of Coomassie brilliant blue G-250 (CBB) binding to proteins in order to develop a protein assay with the maximum possible sensitivity. We found that the neutral ionic species of CBB binds to proteins by a combination of hydrophobic interactions and heteropolar bonding with basic amino acids. On the basis of these findings, we developed a very sensitive hydrophobic assay for proteins (at the nanogram level) using the hydrophobic reagents ammonium sulfate and trichloroacetic acid under pH conditions that increase neutral species concentration in the assay reagent in order to enhance the binding of more CBB dye molecules per protein molecule than in previous CBB-based assays.


Fasting reduces oxidative stress, mitochondrial dysfunction and fibrosis induced by renal ischemia-reperfusion injury.
Food deprivation protects against ischemia-reperfusion (IR) injury through unknown mechanisms. In an experimental rat model of acute IR injury, we found that preoperative fasting for 3 days protects rats from tubular damage and renal functional decline by increasing antioxidant protection independently of the NF-E2-related factor 2 (Nrf2), and by maintaining mitochondrial morphology and function. In addition, further analysis revealed that fasting protects against tubulointerstitial fibrosis. In summary, our results point out to fasting as a robust nutritional intervention to limit oxidative stress and mitochondrial dysfunction in early acute kidney injury and also to promote long-term protection against fibrosis.


Liver transplantation versus liver resection for treatment of neuroendocrine liver metastasis: Appraisal of the current evidence.
Liver transplantation (LT) for neuroendocrine liver metastases (NELM) is still in debate. Studies comparing LT with liver resection (LR) for NELM are scarce, as patient selection is heterogeneous and experience is limited. The goal of this review was to provide a critical analysis of the evidence on LT versus LR in the treatment of NELM. A scoping literature search on LT and LR for NELM was performed with PubMed, including English articles up to March 2023. International guidelines recommend LR for NELM in resectable, well-differentiated tumors in the absence of extrahepatic metastatic disease with superior results of LR compared to systemic or liver-directed therapies. Advanced liver surgery has extended resectability criteria whilst entailing increased perioperative risk and short disease-free survival (DFS). In highly selected patients (based on the Milan criteria) with unresectable NELM, oncologic results of LT are promising. Prognostic factors include tumor biology (G1/G2) and burden, waiting time for LT, patient age and extra-hepatic spread. Based on low-level evidence, LT for low-grade NELM within the Milan criteria resulted in improved DFS and overall survival compared to LR. The benefits of LT were lost in patients beyond the Milan NELM-criteria. With adherence to strict selection criteria especially tumor biology, LT for NELM is becoming a valuable option providing oncologic benefits compared to LR. Recent evidence suggests even stricter selection criteria with regard to tumor biology.


[Direct muscular neurotization].
The authors present a technique of direct muscular neurotization consisting of re-innervation by direct implantation of a nerve into one or several muscles in cases of avulsion of the nerve supplying the muscle or traumatic or surgical avulsion of the neural part of the muscle. The biological basis for this operation is that a denervated muscle can accept a new innervation by a foreign nerve even in an aneural zone because its sensitivity to acetylcholine is present throughout the muscle, while, in a normally innervated muscle, sensitivity to acetylcholine is confined to the motor endplates. The results of 47 cases are presented: 42 of them obtained good or very good results.


A sensitive surface-enhanced Raman spectroscopy detection for gentamicin and tobramycin using γ-Al2O3-modified silver nanoparticles coated with bovine serum albumin as substrate.
Two aminoglycoside antibiotics (AGs), gentamicin (GEN) and tobramycin (TOB), have good antibacterial activity against most pseudomonas aeruginosa and staphylococcus. The molecular structure of these drugs lack chromogenic groups, which brings challenges to their detection. In this project, the detecting methods for GEN and TOB utilizing surface-enhanced Raman spectroscopy (SERS) based on γ-Al2O3-modified silver nanoparticles (AgNPs) coated with bovine serum albumin (BSA) were established. The enhancement factors (EFs) of GEN and TOB were 2.44 × 105 and 2.67 × 106, respectively. The transmission electron microscopy (TEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA) and spectrophotometric techniques were used to characterize the substrate and the combination of the substance with drugs. The pH, the addition amounts for the substrate and coagulant, as well as the mixing time were optimized. On the basis of single factor experiments, a more scientific response surface model was established. The concentrations of GEN and TOB showed good linear relationships with their Raman signals in the ranges of 6.67 × 10-8 - 2.00 × 10-6 and 6.67 × 10-9 - 3.00 × 10-7 mol L-1 respectively. The limits of detection (LODs) were 11.88 and 1.26 nmol L-1 for GEN and TOB, respectively. The methods were used successfully for the samples determination of the two AGs in commercial drugs and meat products.


MACC1 facilitates chemoresistance and cancer stem cell‑like properties of colon cancer cells through the PI3K/AKT signaling pathway.
With regards to colon cancer, resistance to 5‑fluorouracil (5‑FU)‑based chemotherapy and cancer stem cells (CSCs) are considered important factors underlying therapy failure. Metastasis‑associated colon cancer 1 (MACC1) has been associated with poor prognosis and the promotion of metastasis within several types of cancer. However, the biological behavior of MACC1 in chemoresistance and CSC‑like properties remains unclear. In the present study, various methods including gene knockdown, gene overexpression, western blotting, quantitative polymerase chain reaction and MTT assay, have been adopted. According to the results of the present study, MACC1 was depleted in two colon cancer cell lines resistant to 5‑FU; subsequently, CSC‑like properties and 5‑FU sensitivity were investigated. Within 5‑FU‑resistant cells, cell death was facilitated by MACC1 knockdown. Furthermore, sphere formation and the expression levels of pluripotent markers, including cluster of differentiation (CD) 44, CD133 and Nanog were reduced due to MACC1 depletion. Additionally, it was indicated that the phosphoinositide 3‑kinase/protein kinase B signaling pathway may be associated with 5‑FU resistance and CSC‑like properties via MACC1.


Epidermal growth factor and transforming growth factor alpha concentrations in BPH and cancer of the prostate: their relationships with tissue androgen levels.
We measured immunoreactive EGF and TGF alpha in prostate tissue extracts obtained from 19 patients with benign prostatic hyperplasia (BPH) and 19 with cancer of the prostate (CaP). Whilst both BPH and CaP expressed EGF (BPH = 195.61 +/- 19.94 ng g-1 protein; CaP = 235.60 +/- 24.45 ng g-1 protein) and TGF alpha (BPH = 92.57 +/- 7.60 ng g-1 protein; CaP = 100.73 +/- 15.47 ng g-1 protein) in equal concentrations, the levels of EGF in any tissue extract were on average twice those of TGF alpha. Furthermore analysis of the individual growth factor data revealed a direct correlation between EGF and TGF alpha in both BPH (r = 0.72, P < 0.001) and CaP (r = 0.69, P < 0.001). When the tumours were classified according to their Gleason score, a slight but significant increase in growth factor concentrations was noted as the tumour became less differentiated. We also measured the concentrations of testosterone and dihydrotestosterone (DHT) in prostate extracts with a view of elucidating the relationship between androgen and growth factors in this gland. There was a small positive correlation only between testosterone and EGF (r = 0.62, P < 0.05) and testosterone and TGF alpha (r = 0.61, P < 0.05) in CaP. The absence of any similar correlation in BPH where DHT becomes the predominant hormone may suggest an indirect role for testosterone in the regulation of growth factor production.


Infertility and cervical Chlamydia trachomatis infections.
Of the 51 women examined for infertility, 19.6 per cent were found Chl. trachomatis culture-positive. This differs, although not significantly, from the 9 per cent isolation rate among our general gynecological outpatients. The results suggest that Chl. trachomatis should be considered in women with unexplained infertility.


SLC26A4 mutations in patients with moderate to severe hearing loss.
Mutations in SLC26A4 cause either syndromic or nonsyndromic hearing loss. We identified a link between hearing loss and DFNB4 in 3 of the 50 families participating in this study. Sequencing analysis revealed two SLC26A4 mutations, p.V239D and p.S57X, in affected members of the 3 families. These mutations have been previously reported in deaf individuals from the subcontinent, all of whom manifested profound deafness. The patients investigated in our study exhibited moderate to severe hearing loss. Our results show that inactivating SLC26A4 mutations that cause profound deafness can also be involved in the etiology of moderate to severe hearing loss. The type of mutation cannot predict the severity of the hearing loss in all cases, and there may be additional epistatic interactions that could modify the phenotype.


Determination of polyamines in human erythrocytes by capillary gas chromatography with nitrogen-phosphorus detection.
A capillary gas chromatographic method with nitrogen-phosphorus detection is used to determine simultaneously 1,3-diaminopropane, putrescine, cadaverine, spermidine and spermine in human erythrocytes. The compounds are isolated by adsorption on silica and converted into their heptafluorobutyryl derivatives. We give quality-control data and (age-dependent) normal values for 48 apparently healthy controls.


Aeromonas septicaemia in Hong Kong species distribution and associated disease.
During a 5-year study of 2211 patients with clinically significant positive blood cultures in Hong Kong. Aeromonas spp. were isolated in 40 cases. Among 26 episodes in which a single species was isolated. 17 (65.4%) were identified as Aeromonas hydrophila. 8 (30.8%) as A. sobria and one (3.8%) as A. caviae. There were 14 episodes with a mixture of species. Of these, nine (64.3%) were identified as A. hydrophila, two (14.3%) as A. sobria, and two (14.3%) as A. caviae. One (7.1%) was an infection with both A. sobria and A. hydrophila. These polymicrobial infections were usually combined with the presence of Enterobacteriaceae. Hepatobiliary disease was the underlying problem in 24 cases (60.0%) and malignant neoplasia in 14 (35.0%) cases. Most patients presented with fever and leucocytosis. The mortality rate for A. sobria septicaemia was not significantly different from the average rate for all septicaemias. A total of 30 isolates was available for sensitivity testing with 17 antibiotics. More than 86.0% were resistant to ampicillin, and the addition of the beta-lactamase inhibitor sulbactam did not restore its activity. All strains tested were sensitive to cefotaxime, ceftazidime, aztreonam, imipenem, norfloxacin and ciprofloxacin.


[Spontaneous pneumomediastinum: descriptive study of our experience with 36 cases].
Spontaneous pneumomediastinum is defined as a primary process characterized by the presence of air or gas in the mediastinum. We report all the cases of spontaneous pneumomediastinum diagnosed in our hospital between January 1996 and December 2004. We developed a protocol for data collection that included the following: medical history, triggers, signs, radiology, treatment, hospital stay, and complications. During this period we diagnosed 36 cases--25 men (69.4%) and 11 women (27.5%)--with a mean age of 36.8 years (range, 11-90 years) and a mean hospital stay of 8.56 days (range, 1-53 days). The most common clinical presentation was chest pain, either isolated (27%) or with associated dyspnea (19.4%). A triggering factor was identified for 14 patients (38.8%). There was no associated morbidity or mortality. In view of our findings, we concluded that spontaneous pneumomediastinum is an uncommon entity with considerable clinical variability and that correct diagnosis requires a high level of suspicion. Radiography provides the best evidence for diagnosis.


A novel ML protein from Manduca sexta may function as a key accessory protein for lipopolysaccharide signaling.
Lipopolysaccharide (LPS) present on the outer membrane of Gram-negative bacteria is one of the most important pathogen-associated molecular patterns and a potent elicitor in innate immunity. In human, TLR4 (Toll-like receptor 4) and MD-2 (myeloid differiation-2) form a receptor complex to transduce the LPS signal into cells. However, in invertebrates, receptors that recognize LPS have not been determined. Here we report the purification, characterization and cDNA cloning of an ML (MD-2-related lipid-recognition) protein from the tobacco hornworm Manduca sexta. The full-length cDNA of this M. sexta ML protein, named MsML-1, is 532bp with an open reading frame of 456bp that encodes a polypeptide of 151 amino acids containing an ML domain. MsML-1 is a secreted glycoprotein and its mRNA is expressed in fat body and hemocytes. The expression level of MsML-1 mRNA in fat body and hemocytes as well as MsML-1 protein in hemolymph are not induced by immune challenge. Recombinant MsML-1 protein specifically binds to LPS from several Gram-negative bacteria and LPS Re mutant, as well as to lipid A, but not to KDO (2-keto-3-deoxyoctonate). Our results suggest that MsML-1 may function as a key accessory protein for LPS signaling in M. sexta against Gram-negative bacterial infection.


The molecular mechanism of plasma membrane H+-ATPases in plant responses to abiotic stress.
Plasma membrane H+-ATPases (PM H+-ATPases) are critical proton pumps that export protons from the cytoplasm to the apoplast. The resulting proton gradient and difference in electrical potential energize various secondary active transport events. PM H+-ATPases play essential roles in plant growth, development, and stress responses. In this review, we focus on recent studies of the mechanism of PM H+-ATPases in response to abiotic stresses in plants, such as salt and high pH, temperature, drought, light, macronutrient deficiency, acidic soil and aluminum stress, as well as heavy metal toxicity. Moreover, we discuss remaining outstanding questions about how PM H+-ATPases contribute to abiotic stress responses.


An investigation into the physiological relevance of the vagal tachycardia in the anaesthetized dog.
Our aim was primarily to assess whether or not a vagal tachycardia can be elicited in vivo without administration of atropine, and secondly to evaluate whether the dose of atropine, a muscarinic antagonist, determines the magnitude of the tachycardia. Experiments were carried out in the presence of atenolol (2 mg kg(-1)). The vagal tachycardia requires high vagal activity which was induced by noradrenaline infusion (20 microg min(-1)). Two techniques were then used to elicit a tachycardia, vagal section and atropine administration. The increase in blood pressure caused heart rate to fall to 60 +/- 7 beats min(-1) (mean +/- SEM). When the vagi were sectioned (n = 5) heart rate increased by 9 +/- 2 beats min(-1) above the intrinsic rate which was 108 beats min(-1), this increase was not significant. In contrast atropine given (9-20 microg kg(-1)) (n = 5) during high vagal activity increased heart rate by 81 +/- 22 beats min(-1) above the intrinsic rate (P < 0.05). To assess if the dose of atropine affects the magnitude of the vagal tachycardia, the right vagus was stimulated electrically at increasing frequencies (2, 4, 8, 16, 32 Hz) before and after increasing doses of atropine (0.02, 0.05, 1 mg kg(-1)). This reduced the magnitude of the bradycardia; however, the magnitude of the vagal tachycardia was unaffected. The vagal tachycardia cannot be elicited without atropine suggesting that it does not play a significant physiological role.


Surfactant lecithin fatty acid composition and its relationship to the infantile respiratory distress syndrome.
In order to evaluate the role of surfactant lecithin composition in the development of the infantile respiratory distress syndrome (IRDS) we have examined lecithin fatty acid composition from gastric aspirates obtained at the time of delivery from 14 full term healthy infants, 9 control premature infants without respiratory distress, and 16 premature infants who developed IRDS. The latter had significantly reduced concentrations of palmitic acid (48.4 +/- 1.8% vs. 65.3 +/- 1.5% in fullterm and 59.5 +/- 0.8% in control premature infants, P less than 0.001). None of the infants in whom palmitic acid was more than 60% of total lecithin fatty acids developed IRDS, whereas 10 of 11 infants with values below 50% did develop this complication. Lecithin from gastric aspirate was shown to be similar in fatty acid composition to lecithins from tracheal washings and amniotic fluid. Palmitic acid concentrations in lecithins of serial tracheal washings paralleled the clinical course of eight infants with IRDS.


Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells.
During cancer metastasis, circulating tumor cells constantly experience hemodynamic shear stress in the circulation. Cellular responses to shear stress including cell viability and proliferation thus play critical roles in cancer metastasis. Here, we developed a microfluidic approach to establish a circulatory microenvironment and studied circulating human colon cancer HCT116 cells in response to a variety of magnitude of shear stress and circulating time. Our results showed that cell viability decreased with the increase of circulating time, but increased with the magnitude of wall shear stress. Proliferation of cells survived from circulation could be maintained when physiologically relevant wall shear stresses were applied. High wall shear stress (60.5 dyne/cm(2)), however, led to decreased cell proliferation at long circulating time (1 h). We further showed that the expression levels of β-catenin and c-myc, proliferation regulators, were significantly enhanced by increasing wall shear stress. The presented study provides a new insight to the roles of circulatory shear stress in cellular responses of circulating tumor cells in a physiologically relevant model, and thus will be of interest for the study of cancer cell mechanosensing and cancer metastasis.


Acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects.
The German MAK value of 1-methoxypropanol-2 has been fixed at 100 ppm. The aim of this study was to evaluate possible acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects. Twenty subjects were exposed in a crossover design to 100 ppm 1-methoxypropanol-2 and to air in an exposure chamber for 4h. Subjective symptoms were assessed by questionnaire. Olfactory thresholds for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1β and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1β, 6 and 8, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, obtained after exposure. Possible effects were investigated by semiparametric and parametric cross-over analyses. Subjects did not have any subjective irritating symptoms. The olfactory threshold was slightly elevated following exposure to 1-methoxypropanol-2. Mucociliary transport time did not change. Neither concentrations of interleukins in nasal secretions nor mRNA levels except for interleukin 1β were higher after exposure to 1-methoxypropanol-2. In conclusion, the acute exposure to 100 ppm 1-methoxypropanol-2 did not cause clear-cut adverse effects in test subjects.


The STAT signaling profile at the single cell level reveals novel insights in the association of FOXP3+ T regulatory cells with recurrent spontaneous abortions before and after lymphocyte immunotherapy.
Foxp3+ T regulatory cell (Tregs) are central in the pathobiology of recurrent spontaneous abortions (RSA). Signal transducer and activator of transcription (STAT) proteins instruct Treg differentiation and polarization, but the STAT signaling architecture of Tregs in RSA and its modifications by lymphocyte immunotherapy (LIT) are yet unknown. By using single-cell phospho-specific flow cytometry we show that the STAT signaling biosignature of Tregs in women with RSA was characterized by marked downregulation of the IFNα/pSTAT1&5, IL-6/pSTAT1&3 and IL-2/pSTAT5 signaling nodes compared to age-matched fertile females. LIT partially restored all of these signaling axes in Tregs only in women who achieved pregnancy after treatment. Both the pretreatment biosignature of Tregs and its modulations by LIT were associated with therapeutic success. We conclude that STAT signaling pathways in Tregs are actively involved in the pathophysiology of RSA and may serve as a predictive tool for selecting patients who may benefit from LIT.


High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC.
Compromise of genetic information by mutation may result in the dysregulation of cellular growth control and subsequent tumour formation. Xeroderma pigmentosum (XP) is a rare autosomal disease characterized by hypersensitivity of the skin to sunlight and > 1,000-fold increased risk of skin cancers in sun-exposed parts of the body. Cell fusion studies have revealed eight complementation groups in XP (A-G, and an XP-variant form); group C is one of the most common forms of the disease. We have isolated a mouse homologue of the human gene for XP group C and generated XPC-deficient mice by using embryonic stem cell technology. Mice homozygous for the XPC mutant allele (xpcm1/xpcm1) are viable and do not exhibit an increased susceptibility to spontaneous tumour generation at one year of age. However, xpcm1/xpcm1 mice were found to be highly susceptible to ultraviolet-induced carcinogenesis compared with mice heterozygous for the mutant allele (xpcm1/+) and wild-type controls. Homozygous xpcm1 mutant mice also display a spectrum of ultraviolet-exposure-related pathological skin and eye changes consistent with the human disease xeroderma pigmentosum group C.


Phosphorus retention and release by sediments in the eutrophic Mai Po Marshes, Hong Kong.
This study examined the phosphorus retention and release characteristics of sediments in the eutrophic Mai Po Marshes in Hong Kong. Results of chemical fractionation show that the sum of inorganic P pools exceeded 50% of the total sediment P content, with the redox-sensitive iron-bound P (Fe(OOH) approximately P) being the dominant P fraction. Given the considerable average Fe(OOH) approximately P concentration of 912 microg g(-1), Mai Po sediments demonstrated a great potential to release bioavailable P under low sediment redox potentials. This was further supported by the high mean anaerobic P flux of 31.8 mg m(-2)d(-1) recorded in Mai Po sediment cores, indicating the role of bottom sediments as a net P source. Although sediments in Mai Po had appreciable Langmuir adsorption maxima (1642-3582 mg kg(-1)), the high zero equilibrium P concentrations (0.02-0.51 mg L(-1)) obtained suggest that sediment sorption processes would contribute to sustaining the eutrophic conditions in overlying water column even with a further reduction in external P load. Concerted efforts should be made to reduce internal loading of P, especially under reducing conditions, to complement the implementation of zero discharge policy for Deep Bay for effective eutrophication abatement and long-term water quality improvement in the Mai Po Marshes.


Prevalence of Mycoplasma hominis in patients with gynecologic diseases and abortion in the 2nd--3rd month of pregnancy.
The presence of Mycoplasma hominis was investigated in 100 patients with gynecologic diseases, 20 infertility cases and 50 cases of abortion in the 2nd--3rd month of pregnancy. M. hominis could be isolated from the vaginal secretions of 20 patients with gynecologic diseases and of 3 infertility cases. Eighteen M. hominis isolates were recovered from 13 patients with abortion (8 strains from the placenta and 10 from vaginal secretions). High titers (1/64--1/512) of complement fixing antibodies to M. hominis were found in 16 patients with gynecologic diseases, 12 infertility and 17 abortion cases.


Identification and validation of a novel phagocytosis regulators-related signature with potential prognostic and immunotherapeutic value in patients with lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is a malignant tumor that seriously affects the prognosis of patients. Tumor-associated macrophages (TAMs) play a vital role in the tumor microenvironment and can be used as a potential target for tumor therapy, and phagocytosis regulators (PRs) are particularly important in this process. However, the PRs-related signature that can predict the potential prognostic and immunotherapeutic value in patients with LUAD has not been discovered. In this study, we mainly analyzed the effect of phagocytosis regulators on the prognosis of LUAD, and based on multiple screening analyses including differential analysis, univariate Cox analysis, and Lasso analysis, we constructed a prognostic risk model consisting of five genes. To verify the stability of the model, survival analysis and ROC curve verification were carried out through multiple data sets. In addition, we also combined many factors, such as immune infiltrating cells, clinical grouping characteristics, immune examination sites, pro-inflammatory factors, and other factors as well as in vitro cell experiments and clinical tissue samples for further validation analysis. After identifying 29 differentially expressed PRs in LUAD samples, we further constructed a prognostic model consisting of five prognostic signatures (FURIN, KIF23, SASH3, GNPNAT1, and ITGAL). Further survival analysis tests, ROC verification, as well as univariate and multivariate Cox regression analysis showed that the risk score of the model could well predict the prognosis of LUAD patients and could be used as an independent prognostic factor. In addition, we further found that these phagocytic regulators-related signatures were closely related to the immune microenvironment and immunotherapy in LUAD patients, and could well predict the efficacy of immunotherapy in patients. In vitro cell experiments and Immunohistochemistry of clinical tissues showed that the expressions of FURIN, KIF23, SASH3, GNPNAT1 and ITGAL in normal lung cells/tissues and LUAD cells/tissues were consistent with bioinformatics results, and 3 of them had significant differences. Our study identified a novel PRs-related signature that has potential application value in predicting the prognosis of LUAD patients and predicting the efficacy of immunotherapy. This provides a new basis for the prognosis assessment of LUAD patients and provides a novel target for immunotherapy of LUAD patients.


Three-year observational study of immediate post-abortion insertion versus menstrual insertion of etonogestrel contraceptive implant.
This study aimed to estimate the difference in vaginal bleeding pattern, discontinuation rate, and satisfaction between immediate after abortion and menstrual insertions of etonogestrel contraceptive implants. Between May 2013 and November 2015, 66 women were recruited in the abortion group who selected etonogestrel implants as their contraceptive immediately after induced abortion. 84 women who underwent the placement of the etonogestrel implant during their menstrual period were enrolled as the menstrual group. The two groups participated in 3-year follow-up outpatient visits at 1, 6, 12, 24, and 36 months after implantation. The vaginal bleeding pattern, discontinuation rate, satisfaction rate were recorded and compared. No woman had pregnancy over the study period of 3 years. The incidence of amenorrhea/infrequent bleeding did not differ between the two groups after 12, 24, and 36 months of implantation (53.0% vs. 58.4%, 47.8% vs. 51.6%, and 48.6% vs. 55.6%, respectively). In the abortion group, the incidences of frequent/prolonged bleeding were 15.1%, 32.6%, and 27.0% after 12, 24, and 36 months of implantation, respectively, while the other group showed 27.3%, 25.8%, and 20.4%, respectively. After 12 and 24 months, the continuation use rates were 69.7% and 56.1% in the abortion group and 73.8% and 64.2% in the menstrual group. The 12-month satisfaction rate between abortion group and menstrual group was 69.6% versus 72.6%. Statistical analyses show that there was no difference in vaginal bleeding pattern, discontinuation rate or satisfaction between the two groups. Immediately post-abortion may be also a favorable time to undergo etonogestrel implantation.


Stimulator of interferon genes from Asian swamp eel (MaSTING) is involved in host defense against bacterial infection.
Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-associated protein that plays critical roles in innate immunity and pathogenesis of various diseases. To date, teleost STING against viral stimulation has been identified, whereas STING signaling events in fish against bacteria are not well understood. In the present study, the open reading frame (ORF) of STING from Asian swamp eel (Monopterus albus) was cloned (named MaSTING) and its roles in bacterial infection were investigated. Amino acid sequence alignment and phylogenetic analysis revealed that MaSTING had conserved structures with mammalian STING and shared the closest relationship with mandarin fish STING. Subcellular localization analysis showed that MaSTING distributed in the whole cytoplasm and mainly co-localized with ER. Expression pattern analysis found that MaSTING was constitutively expressed in all the examined tissues with the highest expression in the liver and spleen. Post stimulation with bacteria and various PAMPs, the expression of MaSTING was induced at indicated time points in the immune-related organs and isolated peripheral blood leucocytes. Furthermore, the mechanism underlying MaSTING against bacterial infection was further studied. The qPCR analysis showed that MaSTING overexpression promoted 2'3'-cGAMP induced the expression of IFN-1, ISG15, Viperin, Mx, IL-1β and TNF-α. Western blotting assay suggested that MaSTING significantly enhanced the phosphorylation of TANK-binding kinase 1 (TBK1) and p65. MaSTING also significantly increased the luciferase activity of IFN-1 and NF-κB promoters. Taken together, MaSTING is involved in host defense against bacterial infection by inducing the inflammatory response.


Kounis Syndrome: A Case of Vancomycin-Associated Coronary Artery Vasospasm Resulting in Myocardial Infarction.
We describe a case of Kounis syndrome, an allergic reaction causing coronary artery vasospasm, triggered by a vancomycin infusion, in a healthy 32-year-old man. The patient initially presented with an inguinal abscess requiring intravenous vancomycin. During his third infusion, he developed typical chest pain that resolved with cessation of the infusion. Troponin was elevated, and electrocardiogram showed ST elevation, prompting emergent cardiac catheterization that demonstrated normal coronary arteries. The cause of the myocardial infarction was consistent with Kounis syndrome. Diagnosis of Kounis syndrome is important, as prompt cessation of the offending agent is a priority to reduce further cardiac injury.


Academic Productivity Among Underrepresented Minority and Women Urologists at Academic Institutions.
To characterize academic productivity for underrepresented minorities (URMs) vs non-URMs and by gender in Urology. A database was created from 145 Urology residency programs. URM status was determined by origin of name, photo, biography, Twitter, LinkedIn, and Doximity. A PubMed query was performed for publication output. URM status, gender, post-graduate year/years of practice, and Doximity residency rank were factors in multivariable analysis. For residents, the median total publications was 2 [1,5] for URMs and 2 [1,5] for non-URMs (P=.54). The median first/last author publications was 1 [0,2] for URMs and 1 [0,2] for non-URMs (P=.79). The median total publications was 2 [0,4] for women and 2 [1,6] for men (P=.003). The median first/last author publications was 1 [0,2] for women and 1 [0,2] for men (P=.14). For faculty, the median total publications was 12 [3,32] for URMs and 19 [6,45] for non-URMs (P=.0002). The median first/last author publications was 4.5 [1,12] for URMs and 7 [2,20] for non-URM faculty (P=.0002). The median total publications was 11 [5,25] for women and 20 [6,49] for men (P<.0001). The median first/last author publications was 4 [1,11] for women and 8 [2,22] for men (P<.0001). On multivariable analysis, there was no difference in total publications and first/last author publications for URMs vs non-URMs. There remained a difference between genders for residents and faculty with total publications but not first/last author publications (P=.002/P=.10 residents, P=.004/P=.07 faculty). Academic productivity was not different in URMs and non-URMs for both residents and faculty. Men residents and faculty had more total publications compared to women.


Texas TriValve 1.0 : a reverse‑engineered, open model of the human tricuspid valve.
Nearly 1.6 million Americans suffer from a leaking tricuspid heart valve. To make matters worse, current valve repair options are far from optimal leading to recurrence of leakage in up to 30% of patients. We submit that a critical step toward improving outcomes is to better understand the "forgotten" valve. High-fidelity computer models may help in this endeavour. However, the existing models are limited by averaged or idealized geometries, material properties, and boundary conditions. In our current work, we overcome the limitations of existing models by (reverse) engineering the tricuspid valve from a beating human heart in an organ preservation system. The resulting finite-element model faithfully captures the kinematics and kinetics of the native tricuspid valve as validated against echocardiographic data and others' previous work. To showcase the value of our model, we also use it to simulate disease-induced and repair-induced changes to valve geometry and mechanics. Specifically, we simulate and compare the effectiveness of tricuspid valve repair via surgical annuloplasty and via transcatheter edge-to-edge repair. Importantly, our model is openly available for others to use. Thus, our model will allow us and others to perform virtual experiments on the healthy, diseased, and repaired tricuspid valve to better understand the valve itself and to optimize tricuspid valve repair for better patient outcomes.


MiR-199-3p modulates the onset of puberty in rodents probably by regulating the expression of Kiss1 via the p38 MAPK pathway.
The Kiss1 gene plays an indispensable role in modulating the onset of puberty and fertility in mammals. Although an increasing number of genetic and environmental factors that influence reproduction through Kiss1 have been identified, the function of microRNAs, a class of posttranscriptional regulators, in regulating Kiss1 expression remains poorly understood. This study aimed at investigating the mechanism by which Kiss1 expression is regulated by microRNAs. A simplified miRNome screen by a dual-fluorescence reporter system based on Kiss1 was performed to identify microRNAs that affect the expression of Kiss1. The expression patterns of the identified microRNAs during the period of murine sexual development were investigated, and only miR-199-3p was studied further. Aided by bioinformatics algorithms, miR-199-3p was demonstrated to be a repressor of Kiss1 expression, as it blocked the expression of Kiss1 through the p38 MAPK pathway by simultaneously inhibiting several targets in both GT1-7 cells and primary hypothalamic neurons. Both the inhibition of the p38 MAPK pathway by the intracerebroventricular administration of chemical agents in rats and the ectopic expression of miR-199-3p by lentivirus injection in the hypothalamus in mice delayed puberty onset and gonad development. Our results presented a novel regulatory mechanism of puberty onset which the sustained downregulation of miR-199-3p might gradually release the inhibition of the p38 MAPK/Fos/CREB/Kiss1 pathway during puberty development.


A rare complication of severe acute pancreatitis: portal vein compression resulting in an uncontrollable gastric ulcer bleeding.
A 43-year-old male with a diagnosis of severe acute pancreatitis (SAP) was admitted to our hospital. After receiving the step-up approach for three weeks, the patient had a sudden hematemesis (nearly 400 ml). Gastroscopy and computed tomography (CT) were performed on the same day, revealing a gastric ulcer with a hemorrhage and the portal vein was extremely compressed by peripancreatic fluid collections in the retroperitoneal space.


Individual differences in flow proneness are linked to a dopamine D2 receptor gene variant.
Flow is a special mental state characterized by deep concentration that occurs during the performance of optimally challenging tasks. In prior studies, proneness to experience flow has been found to be moderately heritable. In the present study, we investigated whether individual differences in flow proneness are related to a polymorphism of the dopamine D2 receptor coding gene (DRD2 C957T rs6277). This polymorphism affects striatal D2 receptor availability, a factor that has been shown to be related to flow proneness. To our knowledge, this is the first study to investigate the association between this trait and a specific gene variant. In a sample of 236 healthy Hungarian adults, we found that CC homozygotes report higher flow proneness than do T allele carriers, but only during mandatory activities (i.e., studying and working), not during leisure time. We discuss implications of this result, e.g., the potential mediators of the relationship.


Recombinant expression and characterization of L-asparaginase II from a moderately thermotolerant bacterial isolate.
A moderately thermotolerant bacterium belonging to Enterobacteriaceae, which can grow at 44.5 °C, was isolated from cow dung; L-asparaginase II gene was isolated by PCR, cloned, and expressed in pET 20b with pelB leader sequence and 6× Histidine tag at the C-terminal end. The active protein from the soluble sonicated fraction was purified through nickel affinity chromatography. After characterization, the purified protein showed optimum activities at a temperature of 37 °C and in a buffer system of pH 6 to 7. The enzyme exhibited thermostability at 50 °C with a 33% and 28% of activity retention after 45 and 60 min. The kinetic parameters for the enzyme were calculated from Lineweaver-Burk plot, and K(m) and V(max) were 0.89 mM and 0.18 U/mg, respectively.


Effect of electromagnetic radiation modulated by biostructures on the course of alloxan-induced diabetes mellitus in rats.
Exposure of rats with experimental diabetes mellitus to wide-band electromagnetic radiation generated by He-Ne laser and modulated by the pancreas and spleen is informing and phenomenological method prolonging animal life span, normalizing blood glucose level, and promoting regeneration of the pancreas.


Effect of Ozone in Freund's Complete Adjuvant-Induced Arthritis.
This study aims to investigate the effectiveness and reliability of ozone (O3) in Freund's complete adjuvant (FCA)-induced arthritis, an animal model for rheumatoid arthritis. Thirty-six four- to five-month-old male Wistar rats weighing between 274-420 gr were used in this study. Saline was injected into the hind paws of half of these rats, and FCA was injected into the other half. At the end of two weeks, 40 μg of O3 was administered to nine rats from each group twice a week for seven total doses. The rats were followed-up in terms of clinical findings. At the sixth week, the rats were sacrificed and serum malondialdehyde, glutathione peroxidase, and superoxide dismutase levels were measured. In addition, ankle joints were separated for histopathological examination. Significant improvement was observed in terms of hind-paw diameter, severity of arthritis, and histopathological findings of inflammation after O3 treatment in the group with FCA-induced arthritis. Although it was not quite significant, an upward trend was detected in oxidative stress markers with O3 treatment. This study, the first to investigate the effects of systemic O3 on the clinical and histopathological outcomes of rheumatoid arthritis, indicates that O3 is a highly effective and reliable treatment method in FCA-induced arthritis in animal models.


Shaping of infant B cell receptor repertoires by environmental factors and infectious disease.
Antigenic exposures at epithelial sites in infancy and early childhood are thought to influence the maturation of humoral immunity and modulate the risk of developing immunoglobulin E (IgE)-mediated allergic disease. How different kinds of environmental exposures influence B cell isotype switching to IgE, IgG, or IgA, and the somatic mutation maturation of these antibody pools, is not fully understood. We sequenced antibody repertoires in longitudinal blood samples in a birth cohort from infancy through the first 3 years of life and found that, whereas IgG and IgA show linear increases in mutational maturation with age, IgM and IgD mutations are more closely tied to pathogen exposure. IgE mutation frequencies are primarily increased in children with impaired skin barrier conditions such as eczema, suggesting that IgE affinity maturation could provide a mechanistic link between epithelial barrier failure and allergy development.


Anti-cancer potential of flavonoids: recent trends and future perspectives.
Cancer is a major public health concern in both developed and developing countries. Several plant-derived anti-cancer agents including taxol, vinblastine, vincristine, the campothecin derivatives, topotecan, irinotecan and etoposide are in clinical use all over the world. Other promising anti-cancer agents include flavopiridol, roscovitine, combretastatin A-4, betulinic acid and silvestrol. From this list one can well imagine the predominance of polyphenols, flavonoids and their synthetic analogs in the treatment of ovarian, breast, cervical, pancreatic and prostate cancer. Flavonoids present in human diet comprise many polyphenolic secondary metabolites with broad-spectrum pharmacological activities including their potential role as anti-cancer agents. A positive correlation between flavonoids-rich diet (from vegetables and fruits) and lower risk of colon, prostate and breast cancers lead to a question that whether flavonoids mediate the protective effects as chemopreventive agents or can interact with different genes and proteins to play role in chemotherapy. The current review emphasizes onto the therapeutic potential of flavonoids and their synthetic analogs as anti-cancer agents by providing new insights into the factors, regulation and molecular mechanisms along with their significant protein interactions.


Morphological Decomposition in Reading Hebrew Homographs.
The present work investigates whether and how morphological decomposition processes bias the reading of Hebrew heterophonic homographs, i.e., unique orthographic patterns that are associated with two separate phonological, semantic entities depicted by means of two morphological structures (linear and nonlinear). In order to reveal the nature of morphological processes involved in the reading of Hebrew homographs, we tested 146 university students with three computerized experiments, each experiment focusing on a different level of processing. Participants were divided into three experimental groups given that the three experiments used the same stimulus lists. Evidence obtained from the analysis of the participants' processing time and processing accuracy points to a propensity to process heterophonic homographs by default as morpho-syntactically simple rather than complex words. Findings are discussed with reference to assumptions made by Dual-Route models regarding the importance of morphological knowledge in fast and accurate access of written words' representations which mediate the retrieval of their meanings with direct reference to the context in which they occur.


Covalent conjugates of monoclonal antibody and cobra venom factor mediate specific cytotoxicity via alternative pathway of human complement activation.
Because of lack of unspecific toxicity autologous serum is the optimal source of complement for in vitro cell depletion in human bone marrow transplantation. Covalent binding of cobra venom factor to an antibody leads to a specific complement activating conjugate with cytolytic potential independent of the capacity of the antibody to fix complement itself. Therefore this conjugation allows the use of various sera, including human as the source of complement. The kinetics of cobra venom factor-initiated cytolysis is compatible with in vitro treatment of bone marrow prior to transplantation.


Usefulness of circulating E-selectin to early detection of the atherosclerotic process in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).
This cross-sectional analysis evaluated whether determination of E-selectin concentrations could identify deterioration of cardiometabolic risk profile or subclinical atherosclerosis in individuals at low-to-moderate risk included in The Brazilian Longitudinal Study of Adult Health-ELSA-Brasil. A sample of 984 individuals from ELSA-Brasil (35-54 years) without cardiovascular disease or diabetes was stratified according to E-selectin tertiles. Traditional risk factors, inflammatory markers and categories of coronary artery calcium (CAC) scores were evaluated across the tertiles by ANOVA or Chi-squared test. In linear regression models, associations of E-selectin levels with insulin resistance index, adjusted for age, sex and adiposity were tested. The mean age of the participants was 45.8 (SD 4.9) years and 55 % were women. Mean values of age, anthropometric data, biochemical variables and inflammatory status increased across E-selectin tertiles. Also, a gradual deterioration of the cardiometabolic profile was reflected by increments in frequencies (95 % CI) of BMI ≥ 25 kg/m(2) [53.7 % (48.5-58.8), 61.0 % (56.1-66.5) and 64.2 % (59.0-69.4), p = 0.019], hypertension [18.0 % (14.1-22.8), 19.8 % (15.4-24.6) and 24.8 % (20.4-29.9), p = 0.048], pre-diabetes [62.5 % (57.4-68.3), 63.1 % (58.4-69.6) and 73.8 % (68.8-78.3), p = 0.003] and hypertriglyceridemia [22.4 % (17.9-27.2), 27.3 % (22.5-32.8) and 33.4 % (28.3-38.5), p = 0.013]. Insulinemia and HOMA-IR were independently associated with E-selectin concentration. A greater proportion of individuals with CAC scores different from zero was found in the third tertile when compared with the first and second tertiles (16.1 versus 11 %, p = 0.04, respectively). Direct associations of E-selectin with traditional risk factors slightly above their normal ranges, components of the metabolic syndrome, insulin resistance and presence of CAC suggest that this biomarker may indicate an initial atherogenic process.


Design, synthesis and antifungal activity of amide and imine derivatives containing a kakuol moiety.
In continuation of our program to discover new potential antifungal agents, a series of amide and imine derivatives containing a kakuol moiety were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against four plant pathogenic fungi, and structure-activity relationships (SAR) were derived. Compounds 7d, 7e, 7h, 7i and 7r showed obvious inhibitory activity against the corresponding tested fungi at 50 μg/mL. Especially, compounds 7e and 7r displayed more potent antifungal activity against B. cinerea than that of thiabendazole (a positive control). Moreover, compound 7e also exhibited good activity against A. alternata with EC50 values of 11.0 µg/mL, and the value was slightly superior to that of thiabendazole (EC50 = 14.9 µg/mL). SAR analysis showed that the ether group was a highly sensitive structural moiety to the activity and the type as well as position of substituents on benzene ring could make some effects on the activity.


Dosimetry of gamma chamber blood irradiator using Gafchromic EBT film.
Gafchromic films are increasingly being used for dosimetry in medical and industrial applications of ionizing radiation because of their favorable characteristics such as self developing in nature, easy to handle, dose rate independent response, insensitivity to normal room lights, high resolution and insensitivity to variation in the environment conditions. The dosimetry measurements using Gafchromic EBT film, Fricke dosimeter and thermoluminescence (TL) dosimeter were carried out on gamma blood irradiators to establish the suitability of Gafchromic EBT film in such applications. The dose rates determined by Gafchromic EBT film, Fricke dosimeter and TL dosimeter powder are found in good agreement to one another within the uncertainty of measurement. The two-dimensional dose distributions determined using Gafchromic EBT film reflects the expected dose distribution inside the sample compartment of the blood irradiator. The results of this study establish Gafchromic EBT film a suitable dosimeter for routine dosimetry on gamma blood irradiators.


Robust Fault Detection for Switched Fuzzy Systems With Unknown Input.
This paper investigates the fault detection problem for a class of switched nonlinear systems in the T-S fuzzy framework. The unknown input is considered in the systems. A novel fault detection unknown input observer design method is proposed. Based on the proposed observer, the unknown input can be removed from the fault detection residual. The weighted performance level is considered to ensure the robustness. In addition, the weighted performance level is introduced, which can increase the sensibility of the proposed detection method. To verify the proposed scheme, a numerical simulation example and an electromechanical system simulation example are provided at the end of this paper.


The closed and compact domain organization of the 70-kDa human cytochrome P450 reductase in its oxidized state as revealed by NMR.
The NADPH cytochrome P450 reductase (CPR), a diflavin enzyme, catalyzes the electron transfer (ET) from NADPH to the substrate P450. The crystal structures of mammalian and yeast CPRs show a compact organization for the two domains containing FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide), with a short interflavin distance consistent with fast ET from the NADPH-reduced FAD to the second flavin FMN. This conformation, referred as "closed", contrasts with the alternative opened or extended domain arrangements recently described for partially reduced or mutant CPR. Internal domain flexibility in this enzyme is indeed necessary to account for the apparently conflicting requirements of having FMN flavin accessible to both the FAD and the substrate P450 at the same interface. However, how interdomain dynamics influence internal and external ETs in CPR is still largely unknown. Here, we used NMR techniques to explore the global, domain-specific and residue-specific structural and dynamic properties of the nucleotide-free human CPR in solution in its oxidized state. Based on the backbone resonance assignment of this 70-kDa protein, we collected residue-specific (15)N relaxation and (1)H-(15)N residual dipolar couplings. Surprisingly and in contrast with previous studies, the analysis of these NMR data revealed that the CPR exists in a unique and predominant conformation that highly resembles the closed conformation observed in the crystalline state. Based on our findings and the previous observations of conformational equilibria of the CPR in partially reduced states, we propose that the large-scale conformational transitions of the CPR during the catalytic cycle are tightly controlled to ensure optimal electron delivery.


Gene expression profiling of p53-sensitive and -resistant tumor cells using DNA microarray.
Overexpression of wild-type p53 in ECV-304 tumor cells induced extensive apoptosis and the eventual death of nearly all of the cells. We generated ECV-304 cells resistant to p53-induced apoptosis as a strategy to identify novel genes that might be relevant to p53-mediated apoptosis. ECV-304 cells resistant to p53 were isolated by repeated infections with a recombinant p53 adenovirus and were designated as DECV. The expression of 5,730 genes in p53-resistant (DECV) and p53-sensitive ECV-304 cells were profiled by DNA microarray analysis. We report here the expression of 80 genes that differed by 2-fold or more between sensitive and resistant cells upregulated for p53. Many of these differentially expressed genes are regulated by p53 in ECV-304 and H1299 p53-null cells. Our analysis identifies many new potential targets for p53 that play roles in cell cycle regulation, DNA repair, redox control, cell adhesion, apoptosis, and differentiation.


Braak stage and trajectory of cognitive decline in noncognitively impaired elders.
In a previous cross-sectional study, we found that nondemented elderly participants from the Rush Religious Orders Study (RROS) displayed a wide range of Braak neurofibrillary tangle and amyloid plaque pathology similar to that seen in prodromal and frank Alzheimer's disease. Here, we examined longitudinal changes in cognitive domains in subjects from this cohort grouped by Braak stage using linear mixed effects models. We found that the trajectory of episodic memory composite (EMC), executive function composite (EFC), and global cognitive composite scores (GCS: average of EMC and EFC scores) was significantly associated with age at visit over time, but not with Braak stage, apolipoprotein E (APOE) ε4 status or plaque pathology alone. By contrast, the combined effects of Braak stage, APOE status, and age at visit were strongly correlated with the trajectory of EMC, EFC and GCS performance over time. These data suggest that age and APOE ε4 status, rather than Alzheimer's disease-related pathology, play a more prominent role in the trajectory of cognitive decline over time in this elderly nondemented population. However, the findings reported require confirmation in a larger cohort of cases.


Coping with HIV-related stigma in five African countries.
People living with HIV (PLWH) and their families are subjected to prejudice, discrimination, and hostility related to the stigmatization of AIDS. This report examines how PLWH cope with HIV-related stigma in the five southern African countries of Lesotho, Malawi, South Africa, Swaziland, and Tanzania. A descriptive qualitative research design was used to explore the experience of HIV-related stigma of PLWH and nurses in 2004. A total of 43 focus groups were conducted with 251 participants (114 nurses, 111 PLWH, and 26 volunteers). In describing incidents of stigma, respondents reported strategies used or observed to cope with those incidents. Nurse reports of coping strategies that they used as well as observed in HIV-infected patients were coded. Coping strategies used by PLWH in dealing with HIV-related stigma were coded. A total of 17 different self-care strategies were identified: restructuring, seeing oneself as OK, letting go, turning to God, hoping, changing behavior, keeping oneself active, using humor, joining a support or social group, disclosing one's HIV status, speaking to others with same problem, getting counseling, helping others to cope with the illness, educating others, learning from others, acquiring knowledge and understanding about the disease, and getting help from others. Coping appears to be self-taught and only modestly helpful in managing perceived stigma.


Conductive cross-section preparation of non-conductive painting micro-samples for SEM analysis.
Scanning electron microscopy (SEM) is a common method for the analysis of painting micro-samples. The high resolution of this technique offers precise surface analysis and can be coupled with an energy-dispersive spectrometer for the acquisition of the elemental composition. For light microscopy and SEM analysis, the painting micro-samples are commonly prepared as cross-sections, where the micro-sample positioned on the side is embedded in a resin. Therefore, the sequence of its layers is exposed after the cross-section is polished. In common cases outside of cultural heritage, a conductive layer is applied on the polished side, but in this field, the measurements are mostly done in low-vacuum SEM (LV-SEM). Although the charging effect is reduced in LV-SEM, it can still occur, and can hardly be prevented even with carbon tape or paint. This work presents two conductive cross-section preparation methods for non-conductive samples, which reduce charging effects without impairing the sample integrity.


Evaluation of the relationship between caries indices and salivary secretory IgA, salivary pH, buffering capacity and flow rate in children with Down's syndrome.
The aim of this study was to compare the caries prevalence and salivary secretory IgA (sIgA), salivary pH, buffering capacity and flow rate between Down's syndrome (DS) and control subjects. Seventy-three institutionalised children with DS and 70 normal children aged 7-12 years old were included in this study. Tooth-brushing habits and daily dietary sugar exposures of the children, family income and education levels of the parents were recorded. DMFS and dfs scores were assessed according to the World Health Organisation's criteria and stimulated whole saliva samples were collected. Salivary sIgA levels were determined by radial immunodiffusion technique, the average salivary flow rate was measured from the total volume, and salivary pH and buffering capacity were determined using a pH micro-electrode. All data were analysed using SPSS version 11.0. The DMFS and dfs scores were significantly lower in the DS group than the control group (P < 0.05). Otherwise, the difference in plaque scores between the DS and control groups was not statistically significant (P > 0.05). There were no significant differences in tooth-brushing habits and daily dietary sugar exposures of the children, family income and education levels of the parents between the two groups (P > 0.05). Salivary sIgA levels were significantly higher in the DS group (P < 0.05). Salivary pH, buffering capacity and flow rate were quite similar in both the DS and control groups (P > 0.05). In conclusion, the patients with DS had a significantly lower prevalence of caries and significantly higher levels of salivary sIgA in this study. This finding tends to support the hypothesis that higher levels of salivary sIgA may protect against dental caries.


Better resolving of anti-CD38 antibody interference with blood compatibility testing by using manual polybrene method compared with dithiothreitol-pretreatment indirect antiglobulin test.
It is advised to pretreat the reagent erythrocytes with Dithiothreitol (DTT) to denature the surface CD38 to prevent anti-CD38 monoclonal antibodies (MoAb) from interfering with the blood compatibility test. Anti-CD38 has little impact on the Polybrene test, but it is still unknown how sensitive it is to detect irregular antibodies and how effective it is when compared to the standard DTT-based method. Twenty-one patients receiving daratumumab (N = 13) and isatuximab (N = 8) had their serum collected. Standard anti-sera (anti-c, D, E, Fyb , Jka , M, Mia ) with serial dilution were added to patients' serum. Antibody screening tests were performed simultaneously using the manual polybrene method (MP) and DTT-pretreated, automatic indirect antiglobulin test (DTT-IAT) to compare the detection sensitivity. These two methods' operating times and costs were also analyzed. Both MP and DTT-IAT can overcome the interference caused by anti-CD38 MoAb. However, MP is more sensitive in detecting anti-M and anti-Mia and is comparable to DTT-IAT in detecting other antibodies. In terms of cost and operating time, MP is also far superior to DTT-IAT. MP is a cost-effective alternative to DTT-IAT in resolving anti-CD38 interference and is especially suitable for populations with a high prevalence of anti-M and anti-Mia . However, both methods have a well-known drawback of low detection sensitivity for anti-K, and K-units should be provided to patients to prevent hemolytic transfusion reactions.


Aromatic Polyketides from a Symbiotic Strain Aspergillus fumigatus D and Characterization of Their Biosynthetic Gene D8.t287.
The chemical investigation of one symbiotic strain, Aspergillus fumigatus D, from the coastal plant Edgeworthia chrysantha Lindl led to the isolation of eight compounds (1-8), which were respectively identified as rubrofusarin B (1), alternariol 9-O-methyl ether (2), fonsecinone D (3), asperpyrone A (4), asperpyrone D (5), fonsecinone B (6), fonsecinone A (7), and aurasperone A (8) by a combination of spectroscopic methods (1D NMR and ESI-MS) as well as by comparison with the literature data. An antimicrobial assay showed that these aromatic polyketides exhibited no remarkable inhibitory effect on Escherichia coli, Staphyloccocus aureus and Candida albicans. The genomic feature of strain D was analyzed, as well as its biosynthetic gene clusters, using antibiotics and Secondary Metabolite Analysis Shell 5.1.2 (antiSMASH). Plausible biosynthetic pathways for dimeric naphtho-γ-pyrones 3-8 were first proposed in this work. A non-reducing polyketide synthase (PKS) gene D8.t287 responsible for the biosynthesis of these aromatic polyketides 1-8 was identified and characterized by target gene knockout experiment and UPLC-MS analysis.


Long-term follow-up of recipients of allogeneic bone marrow grafts reveals no progressive telomere shortening and provides no evidence for haematopoietic stem cell exhaustion.
Accelerated telomere shortening has been proposed as a possible long-term risk of allogeneic bone marrow transplantation (allo-BMT). In this study we monitored telomere length in white blood cells (WBC), granulocytes, and naïve and memory CD4+ T lymphocytes in recipients of allo-BMT at long-term follow-up. Peripheral blood was collected from 10 allo-BMT recipients and donors at a median interval of 18 years after allo-BMT. Telomere length was determined using Southern blot analysis. Similar to results previously reported at short-term follow-up, a small difference in telomere length (0.1-0.3 kb) between recipients and donors was detected in WBC, granulocytes and naïve CD4+ T cells. Our data therefore provide no evidence for sustained telomere shortening in leucocytes, and render the possibility of long-term haematopoietic graft failure unlikely. In addition, we observed two phenomena that may be related to involution of the thymus. First, the number of naïve CD4+ T cells in the blood was significantly lower in recipients (0.4 x 10(9)/l) than in donors (0.7 x 10(9)/l) (P < 0.05). Second, telomeres in memory CD4+ T cells from recipients were on average 0.6 kb shorter than those from donors (P = 0.01). The latter may be related to the reported rapid peripheral expansion of memory T cells immediately after transplantation.


Characteristics of airway resistance in obstructive sleep apnea patients with asthma on oscillometry.
Asthma and obstructive sleep apnea (OSA) are prevalent chronic respiratory disorders with a high tendency to coexist. Both diseases involve increased airway resistance in the upright position because of narrow upper or lower airways. Moreover, there is a marked increase in airway resistance in the supine position in patients with OSA. We verified the characteristics of OSA in combination with asthma. Airway resistance was measured by oscillometry in the upright and supine position in 11 healthy participants (control), 59 patients with OSA alone, and 33 OSA patients with asthma (coexistence) in the hospital between April 2014 and July 2020. We compared the differences in airway resistance between the upright and supine positions among the three groups. In addition, we performed cephalometry to evaluate the upper airway structure in patients with OSA alone and in patients with both OSA and asthma. A marked increase in airway resistance due to postural change was observed in the "OSA alone" group compared to that in the control group. However, this was not observed in the "coexistence" and control groups. Moreover, the "coexistence" group had fewer structural abnormalities in the upper airway than the "OSA alone" group on cephalometry. The airway resistance of patients with OSA alone markedly increased with posture change because of upper airway abnormalities. However, there was a smaller increase with postural changes in OSA patients with asthma, suggesting the possibility of a smaller degree of upper airway abnormality compared to patients with OSA alone. This study is approved by the research ethics committee of the Shinshu University School of Medicine (permission number: 4272).


Corrigendum to "Antidiabetic, antioxidant and antimicrobial activities of extracts of Tephrosia bracteolata leaves" [Heliyon 5 (8) (August 2019) e02275].
[This corrects the article DOI: 10.1016/j.heliyon.2019.e02275.].


Estrogen-induced downregulation of TASK-1 expression through estrogen receptor β in N2A cells.
Our previous data revealed that reduction of TASK-1 expression, as a consequence of exposure to 17β-estradiol, could participate in neuroprotective effects in N2A cells. However, it is unclear which estrogen receptor underlies these effects of 17β-estradiol. In this study, the knockdown experiments are carried out to clarify the estrogen receptor responsible for effects of estrogen on TASK-1 channels. Subsequently, data from QPCR measurements reveal that estrogen receptor β (ERβ), but not estrogen receptor α, serves as a binding target for 17β-estradiol after a 48-h treatment. The current result suggests the implication of the ERβ-dependent manner in the pro-proliferative action of estrogen via TASK-1 channels.


Formulation of lemongrass oil (Cymbopogon citratus)-loaded solid lipid nanoparticles: an in vitro assessment study.
Cymbopogon citratus (DC) stapf. (Gramineae) is a herb known worldwide as lemongrass. The oil obtained, i.e., lemongrass oil has emerged as one among the most relevant natural oils in the pharmaceutical industry owing to its extensive pharmacological and therapeutic benefits including antioxidant, antimicrobial, antiviral and anticancer properties. However, its usage in novel formulations is constrained because of its instability and volatility. To address these concerns, the present study aims to formulate lemongrass-loaded SLN (LGSLN) using hot water titration technique. In the Smix, Tween 80 was selected as a surfactant component, while ethanol was taken as a co-surfactant. Different ratios of Smix (1:1, 1:2, 1:3, 2:1 and 3:1) were utilized to formulate LG-loaded SLN. The results indicated the fact that the LGSLN formulation (abbreviated as LGSLN1), containing lipid phase 10% w/w (i.e., LG 3.33% and SA 6.67%), Tween 80 (20% w/w), ethanol (20% w/w) and distilled water (50% w/w), revealed suitable nanometric size (142.3 ± 5.96 nm) with a high zeta potential value (- 29.12 ± 1.7 mV) and a high entrapment efficiency (77.02 ± 8.12%). A rapid drug release (71.65 ± 5.33%) was observed for LGSLN1 in a time span of 24 h. Additionally, the highest values for steady-state flux (Jss; 0.6133 ± 0.0361 mg/cm2/h), permeability coefficient (Kp; 0.4573 ± 0.0141 (cm/h) × 102) and enhancement ratio (Er; 13.50) was also conferred by LGSLN1. Based on in vitro study results, the developed SLN appeared as a potential carrier for enhanced topical administration of lemongrass oil. The observed results also indicated the fact that the phyto-cosmeceutical prospective of the nanolipidic carrier for topical administration of lemongrass oil utilizing pharmaceutically acceptable components can be explored further for widespread clinical applicability. The online version contains supplementary material available at 10.1007/s13205-023-03726-5.


Assessments and admissions during the first 6 years of a UK medium secure DSPD service.
Offenders with personality disorder represent a considerable burden on mental health and criminal justice services. Millfields Unit was one of the pilot medium secure units (MSUs) established by the UK Department of Health and Ministry of Justice to provide dedicated services for such individuals. Our study aimed to describe a complete cohort of referrals made to the service and to explore decisions on admissions to the Unit. File review was used to collect a structured data set of information on the first 158 referrals. These were then analysed descriptively and inferentially. Previous psychological treatment in prison and evidence of motivation for further treatment were the strongest predictors of admission to the service. People admitted showed evidence of more extensive criminal histories, prior treatment failure and higher level of risk than those accepted into conventional medium secure units. Despite the stated purpose of the units being for people with personality disorder, a high number of patients with a primary diagnosis of psychotic illness were referred. The new service accepted a high-risk group of people with personality disorder whose needs would not otherwise have been met.


Psychosis as presenting symptom in adult-onset Hallervorden-Spatz syndrome.
Hallervorden-Spatz syndrome is characterized by pyramidal and extrapyramidal signs, and dysarthria and dementia. Psychiatric symptomatology can emerge in the course of the disorder. Mutations in the pantothenate kinase 2 gene have been found in many cases. We report a case with psychosis as sole presenting symptom. A 41-year-old man presented with change in behavior and paranoid delusional ideation. Six months later, spasticity, extrapyramidal rigidity and dysarthria were added to the picture. Eventually, the patient became mute and wheel-chair bound. The brain magnetic resonance imaging (MRI) was consistent with iron depositions in the globus pallidus and substantia nigra. In this case, the combination of clinical and MRI findings was consistent with Hallervorden-Spatz syndrome. The combination of psychiatric and MRI findings should lead to further neurological investigation.


A new strategy for lipid production by mix cultivation of Spirulina platensis and Rhodotorula glutinis.
Mix cultivation of microalgae (Spirulina platensis) and yeast (Rhodotorula glutinis) for lipid production was studied. Mixing cultivation of the two microorganisms significantly increased the accumulation of total biomass and total lipid yield. Dissolved oxygen and medium components in the mixed fermentation medium were analyzed. Mix cultivation in monosodium glutamate wastewater was further studied. Result indicated 1,600 mg/L of biomass was obtained and 73% of COD were removed.


Formation and control of disinfection byproducts and toxicity during reclaimed water chlorination: A review.
Chlorination is essential to the safety of reclaimed water; however, this process leads to concern regarding the formation of disinfection byproducts (DBPs) and toxicity. This study reviewed the formation and control strategies for DBPs and toxicity in reclaimed water during chlorination. Both regulated and emerging DBPs have been frequently detected in reclaimed water during chlorination at a higher level than those in drinking water, indicating they pose a greater risk to humans. Luminescent bacteria and Daphnia magna acute toxicity, anti-estrogenic activity and cytotoxicity generally increased after chlorination because of the formation of DBPs. Genotoxicity by umu-test and estrogenic activity were decreased after chlorination because of destruction of toxic chemicals. During chlorination, water quality significantly impacted changes in toxicity. Ammonium tended to attenuate toxicity changes by reacting with chlorine to form chloramine, while bromide tended to aggravate toxicity changes by forming hypobromous acid. During pretreatment by ozonation and coagulation, disinfection byproduct formation potential (DBPFP) and toxicity formation potential (TFP) occasionally increase, which is accompanied by DOC removal; thus, the decrease of DOC was limited to indicate the decrease of DBPFP and TFP. It is more important to eliminate the key fraction of precursors such as hydrophobic acid and hydrophilic neutrals. During chlorination, toxicities can increase with the increasing chlorine dose and contact time. To control the excessive toxicity formation, a relatively low chlorine dose and short contact time were required. Quenching chlorine residual with reductive reagents also effectively abated the formation of toxic compounds.


A selective comprehensive reversed-phase×reversed-phase 2D-liquid chromatography approach with multiple complementary detectors as advanced generic method for the quality control of synthetic and therapeutic peptides.
There is a huge, still increasing market for synthetic and therapeutic peptides. Their quality control is commonly based on a generic reversed-phase liquid chromatography (RPLC) method with C18 stationary phase and acetonitrile gradient with 0.1% trifluoroacetic acid in the mobile phase. It performs exceptionally well for a wide variety of impurities, yet structurally closely related impurities with similar sequences, not resolved in preparative RPLC, may easily coelute in the corresponding QC run as well. To address this problem an advanced generic 2D-LC impurity profiling method was developed in this work. It employs a selective comprehensive (high resolution sampling) RP×RP 2D-LC separation using a 100×2.1 mm ID column with the common acidic generic gradient in the first dimension, while RPLC under basic pH on a short 30×3 mm ID column is used in the second dimension. Recording data with a UV detector at 215 nm after 1D separation provides the common generic 1D chromatogram. However, after the 2D separation a flow splitter enabled recording of the signals of complementary detectors comprising a diode array detector (DAD) in-line with a charged aerosol detector (CAD) and a quadrupole-time-of-flight (QTOF) mass spectrometer (MS) with an electrospray ionization (ESI) source. Generic conditions of this 2D-LC method have been established through optimization of 2D stationary and mobile phase considering different pH values and buffer concentrations. The orthogonal separation principle has been documented by a number of therapeutic peptides including Exenatide, Octreotide, Cyclosporine A and Oxytocin as well as some other proprietary synthetic peptides. The information density can be further enhanced by using the QTOF-MS detector by data independent acquisition with SWATH. Through this sequential window acquisition of all theoretical fragment ion mass spectra it became possible to collect MS/MS data comprehensively in the high-resolution sampling window, thus enabling the extraction of 2D-EICs from fragment ions and the generation of 2D-contour plots of all product ions. Using Oxytocin as an example for an important therapeutic peptide, the ability of this advanced generic sRP-UV×RP-DAD-CAD-ESI-QTOF-MS/MS method with SWATH for peptide quality control is discussed.


On the reversal by deoxyribonucleic acid of the binding of adriamycin to cardiolipin-containing liposomes.
The binding of the cytotoxin adriamycin (doxorubicin) to phospholipids, DNA, and RNA was investigated using (i) fluorescence quenching by this drug of liposomes containing pyrene-labeled phospholipids and (ii) monomolecular cardiolipin films on an air/water interface. In accordance with previous studies, our fluorescence experiments revealed that the acidic phospholipids, phosphatidylglycerol, phosphatidylmethanol, and phosphatidic acid all have high and comparable affinities to adriamycin mainly due to electrostatic interactions whereas binding to phosphatidylcholine was much weaker. Highest affinity, however, was possessed by cardiolipin. Addition of 4 mM CaCl2 reduced the binding of adriamycin to the above lipids. Moreover, in the presence of calcium the affinity of the drug to the different lipids was similar. Ca2+ concentrations > 100 microM began to reverse the binding of adriamycin to cardiolipin-containing liposomes whereas lower concentrations had only an insignificant effect. The association of adriamycin with DNA, RNA, and cardiolipin was then compared by observing the reversal of the cytotoxin-cardiolipin association by nucleic acids. The affinity of adriamycin was found to decrease in the sequence DNA > cardiolipin > RNA with relative affinities of 7.8, 2.3, and 1, respectively. Penetration of the drug into cardiolipin monolayers spread on an air/water interface resulted in an increase in surface pressure pi whereas only a very weak increase was observed using dimyristoylphosphatidylcholine films. Removal of adriamycin from lipid monolayers was achieved by adding DNA into the aqueous subphase. Similar to the fluorescence quenching studies increase in pi after the inclusion of adriamycin into the aqueous subphase was significantly reduced in the presence of Ca2+ concentrations > 100 microM, whereas lower concentrations had only an insignificant effect. Residual drug-phospholipid interactions in the lipid monolayer observed in the presence of Ca2+ were also reversed by DNA.


Comparative yield of molecular diagnostic algorithms for autism spectrum disorder diagnosis in India: evidence supporting whole exome sequencing as first tier test.
Autism spectrum disorder (ASD) affects 1 in 100 children globally with a rapidly increasing prevalence. To the best of our knowledge, no data exists on the genetic architecture of ASD in India. This study aimed to identify the genetic architecture of ASD in India and to assess the use of whole exome sequencing (WES) as a first-tier test instead of chromosomal microarray (CMA) for genetic diagnosis. Between 2020 and 2022, 101 patient-parent trios of Indian origin diagnosed with ASD according to the Diagnostic and Statistical Manual, 5th edition, were recruited. All probands underwent a sequential genetic testing pathway consisting of karyotyping, Fragile-X testing (in male probands only), CMA and WES. Candidate variant validation and parental segregation analysis was performed using orthogonal methods. Of 101 trios, no probands were identified with a gross chromosomal anomaly or Fragile-X. Three (2.9%) and 30 (29.7%) trios received a confirmed genetic diagnosis from CMA and WES, respectively. Amongst diagnosis from WES, SNVs were detected in 27 cases (90%) and CNVs in 3 cases (10%), including the 3 CNVs detected from CMA. Segregation analysis showed 66.6% (n = 3 for CNVs and n = 17 for SNVs) and 16.6% (n = 5) of the cases had de novo and recessive variants respectively, which is in concordance with the distribution of variant types and mode of inheritance observed in ASD patients of non-Hispanic white/ European ethnicity. MECP2 gene was the most recurrently mutated gene (n = 6; 20%) in the present cohort. Majority of the affected genes identified in the study cohort are involved in synaptic formation, transcription and its regulation, ubiquitination and chromatin remodeling. Our study suggests de novo variants as a major cause of ASD in the Indian population, with Rett syndrome as the most commonly detected disorder. Furthermore, we provide evidence of a significant difference in the diagnostic yield between CMA (3%) and WES (30%) which supports the implementation of WES as a first-tier test for genetic diagnosis of ASD in India.


Calcium-Permeable Channels in Tumor Vascularization: Peculiar Sensors of Microenvironmental Chemical and Physical Cues.
Calcium (Ca2+)-permeable channels are key players in different processes leading to blood vessel formation via sprouting angiogenesis, including endothelial cell (EC) proliferation and migration, as well as in controlling vascular features which are typical of the tumor vasculature.In this review we present an up-to-date and critical view on the role of Ca2+-permeable channels in tumor vascularization, emphasizing on the dual communication between growth factors (mainly VEGF) and Ca2+ signals. Due to the complexity of the tumor microenvironment (TME) as a source of multiple stimuli acting on the endothelium, we aim to discuss the close interaction between chemical and physical challenges (hypoxia, oxidative stress, mechanical stress) and endothelial Ca2+-permeable channels, focusing on transient receptor potential (TRP), store-operated Ca2+ channels (SOCs), and mechanosensitive Piezo channels. This approach will depict their crucial contribution in regulating key properties of tumor blood vessels, such as recruitment of endothelial progenitors cells (EPCs) in the early steps of tumor vascularization, abnormal EC migration and proliferation, and increased vascular permeability. Graphical abstract depicting the functional role of Ca2+-permeable TRP, SOCs and Piezo channels in the biological processes regulating tumor angiogenesis in presence of both chemical (oxidative stress and oxygen levels) and mechanical stimuli (ECM stiffness). SOCs store-operated Ca2+ channels, TRPA transient receptor potential ankyrin, TRPV transient receptor potential vanilloid, TRPC transient receptor potential canonical, TRPM transient receptor potential melastatin, TRPM transient receptor potential vanilloid, O2 oxygen, ECM extracellular matrix.


Effects of betamethasone on plasma levels of estriol, cortisol and HCS in late pregnancy.
The effect of a single dose of betamethasone on the maternal plasma concentration of estriol and cortisol was studied. The concentration of estriol decreased rapidly. A maximal suppression of about 70 per cent was seen after 6-24 hours. A similar influence on the maternal plasma concentration of cortisol was observed. HCS (human chorionic somatomammotropin) was not influenced by betamethasone. These facts have to be taken into consideration after treatment with synthetic corticosteroids in high risk pregnancies.


Maintaining quality of health services after abolition of user fees: a Uganda case study.
It has been argued that quality improvements that result from user charges reduce their negative impact on utilization especially of the poor. In Uganda, because there was no concrete evidence for improvements in quality of care following the introduction of user charges, the government abolished user fees in all public health units on 1st March 2001. This gave us the opportunity to prospectively study how different aspects of quality of care change, as a country changes its health financing options from user charges to free services, in a developing country setting. The outcome of the study may then provide insights into policy actions to maintain quality of care following removal of user fees. A population cohort and representative health facilities were studied longitudinally over 3 years after the abolition of user fees. Quantitative and qualitative methods were used to obtain data. Parameters evaluated in relation to quality of care included availability of drugs and supplies and; health worker variables. Different quality variables assessed showed that interventions that were put in place were able to maintain, or improve the technical quality of services. There were significant increases in utilization of services, average drug quantities and stock out days improved, and communities reported health workers to be hardworking, good and dedicated to their work to mention but a few. Communities were more appreciative of the services, though expectations were lower. However, health workers felt they were not adequately motivated given the increased workload. The levels of technical quality of care attained in a system with user fees can be maintained, or even improved without the fees through adoption of basic, sustainable system modifications that are within the reach of developing countries. However, a trade-off between residual perceptions of reduced service quality, and the welfare gains from removal of user fees should guide such a policy change.


Tipranavir.
Tipranavir is a potent and selective non-peptidic HIV-1 protease inhibitor with a markedly improved resistance profile compared with traditional, peptidomimetic protease inhibitors. The presence of five or fewer protease gene mutations or one or two protease inhibitor resistance-associated mutations (PRAMs) is associated with reduced susceptibility to currently available protease inhibitors. However, 16-20 mutations (including three or more PRAMs) may be needed to confer resistance to tipranavir. Tipranavir-based therapy achieved sustained viral suppression for more than 48 weeks in a small phase II trial in multiple protease inhibitor-experienced HIV-infected patients. A large dose-finding study demonstrated potent virological reduction through 14 days of functional monotherapy in heavily pretreated HIV-infected patients with 6 to >20 protease gene mutations at baseline. Two large, ongoing, phase III trials in patients with multi-drug resistant HIV infection are comparing the efficacy of tipranavir/ritonavir 500/200mg twice daily plus a patient-individualised background antiretroviral regimen versus other ritonavir-boosted protease inhibitor regimens. In general, tipranavir has been well tolerated in clinical trials. As with other protease inhibitors, the most common adverse events with tipranavir have been gastrointestinal disturbances.


Diagnostic imaging of the equine fetlock region using radiography and ultrasonography. Part 2: the bony disorders.
The metacarpophangeal/metatarsophalangeal (fetlock) joint in the horse is commonly associated with equine lameness and diagnostic imaging is routinely used to investigate disorders of the joint and its surrounding tissues. This review describes the osseous disorders of the fetlock as well as the technical aspects of taking radiographic and ultrasonographic images of the different lesions. In current clinical practice, a combination of radiography and ultrasonography is still the most frequently used approach to arrive at a diagnosis.


A Murine Incisional Fetal Wound-Healing Model to Study Scarless and Fibrotic Skin Repair.
The ideal response to skin injury is the complete regeneration of normal tissue without scar formation. This regenerative response is known to occur at early stages of embryonic development but is lost as the skin becomes more mature. In more developed skin, the wound-healing response is suboptimal and results in the formation of scar tissue. Scar tissue can be a significant clinical concern, causing skin dysfunction as well as psychosocial issues related to poor aesthetic outcomes. Mouse models of fetal wound healing can be useful for understanding what regulatory pathways lead to skin regeneration and scarless healing in less developed skin or scarring and fibrotic healing in more developed skin. Here, a reproducible incisional wound model in developing mice is described that our lab has used repeatedly to study scarless and fibrotic fetal wound healing.