Organized B cell sites in cartilaginous fishes reveal the evolutionary foundation of germinal centers.
The absence of germinal centers (GCs) in cartilaginous fishes lies at odds with data showing that nurse sharks can produce robust antigen-specific responses and affinity mature their B cell repertoires. To investigate this apparent incongruity, we performed RNA sequencing on single nuclei, allowing us to characterize the cell types present in the nurse shark spleen, and RNAscope to provide in situ cellular resolution of key marker gene expression following immunization with R-phycoerythrin (PE). We tracked PE to the splenic follicles where it co-localizes with CXCR5high centrocyte-like B cells and a population of putative T follicular helper (Tfh) cells, surrounded by a peripheral ring of Ki67+ AID+ CXCR4+ centroblast-like B cells. Further, we reveal selection of mutations in B cell clones dissected from these follicles. We propose that the B cell sites identified here represent the evolutionary foundation of GCs, dating back to the jawed vertebrate ancestor.


Nodular granulomatous Pneumocystis carinii pneumonia in a bone marrow transplant recipient. Case report.
We report a case of nodular granulomatous Pneumocystis carinii pneumonia following bone marrow transplantation. The patient was a 40-year-old man who had undergone bone marrow transplantation for myeloblastic acute leukemia. He presented with fever, dyspnea and bilateral diffuse nodular infiltration of the lungs. Bronchoalveolar lavage was negative. Open lung biopsy was performed. Histological examination revealed a granulomatous reaction with central necrosis surrounded by epithelioid and giant cells. Toluidine blue and Gomori-Grocott stains identified a few P. carinii. Mycobacterial and fungal cultures were negative. A granulomatous reaction is rarely observed and almost only in HIV-infected patients. To our knowledge this is the first description in a bone marrow transplant recipient.


Occupational exposure to organophosphate esters in e-waste dismantling workers: Risk assessment and influencing factors screening.
Organophosphate esters (OPEs) are increasingly added in electronic products as alternative flame retardants, which may result in high occupational exposure of electronic waste recycling employees. This study investigated occupational exposure to OPEs in an e-waste recycling site in northern China, with intent to explore the impacts of occupational exposure and dismantling manipulation mode. Human urine samples from three sites with different distances from the core dismantling area, including employees from family workshops and plants with centralized management and residents from nearby areas, were collected and analyzed for OPEs' metabolites (mOPEs). The urinary ∑mOPEs' median concentrations (0.910 ng/mL) of all employees were significantly higher than those of residents in Ziya Town (0.526 ng/mL) and Jinghai downtown (0.600 ng/mL), suggesting the risk of occupational OPEs' exposure associated with e-waste dismantling. However, the spatial variation was insignificant for residents with different distances from the e-waste recycling site. Besides, OPEs' exposure levels were significantly affected by manipulation modes and the urinary ∑mOPEs' median concentrations in the employees of family workshops (1.05 ng/mL) were significantly higher than those in plants with centralized management (0.667 ng/mL). The result suggests that mechanical dismantling and active ventilating measures can reduce the OPEs' occupational exposure risk. Moreover, ∑mOPEs were higher in volunteers with age above 50 years old and in the underweight subgroup. Finally, different categories of mOPEs in human urine showed associations with corresponding OPEs in dust samples in the same area.


Beta-D-xylosidase from Selenomonas ruminantium: thermodynamics of enzyme-catalyzed and noncatalyzed reactions.
Beta-D-Xylosidase/alpha-L-arabinofuranosidase from Selenomonas ruminantium is the most active enzyme known for catalyzing hydrolysis of 1,4-beta-D: -xylooligosaccharides to D-xylose. Temperature dependence for hydrolysis of 4-nitrophenyl-beta-D-xylopyranoside (4NPX), 4-nitrophenyl-alpha-L-arabinofuranoside (4NPA), and 1,4-beta-D-xylobiose (X2) was determined on and off (k (non)) the enzyme at pH 5.3, which lies in the pH-independent region for k (cat) and k (non). Rate enhancements (k (cat)/k (non)) for 4NPX, 4NPA, and X2 are 4.3 x 10(11), 2.4 x 10(9), and 3.7 x 10(12), respectively, at 25 degrees C and increase with decreasing temperature. Relative parameters k (cat) (4NPX)/k (cat) (4NPA), k (cat) (4NPX)/k (cat) (X2), and (k (cat)/K (m))(4NPX)/(k (cat)/K (m))(X2) increase and (k (cat)/K (m))(4NPX)/(k (cat)/K (m))(4NPA), (1/K (m))(4NPX)/(1/K (m))(4NPA), and (1/K (m))(4NPX)/(1/K (m))(X2) decrease with increasing temperature.


The Impacts of Two Gender-Transformative Interventions on Early Adolescent Gender Norms Perceptions: A Difference-in-Difference Analysis.
Inequitable gender norms are widespread and can be harmful to the wellbeing of adolescents. This study estimates the effects of two gender-transformative interventions, Semangat Dunia Remaja or Teen Aspirations (SETARA) and Growing Up Great! (GUG!), on gender norms perceptions and attitudes among very young adolescents in poor urban settings in Bandar Lampung, Semarang, Denpasar (Indonesia), and Kinshasa (Democratic Republic of the Congo). The study draws from the longitudinal Global Early Adolescent Study, using a quasi-experimental design to evaluate the interventions. Data collection took place between 2017 and 2020. Our analytical samples included 2,159 adolescents in Kinshasa and 3,335 in Indonesia. We conducted a difference-in-difference analysis using generalized estimation equations and generalized linear models, after stratification by site and sex. The interventions shifted a range of gender perceptions, although effects varied by program, city, and sex. SETARA shifted gender-normative perceptions related to traits, roles, and relations, while GUG! effects were more concentrated on attitudes toward chore sharing. SETARA was most effective in Semarang and Denpasar, but not in Bandar Lampung. In addition, both interventions were more consistently effective for girls than boys. Gender-transformative interventions can effectively promote gender equality in early adolescence, but effects are program-specific and context-specific. Our findings emphasize the importance of defined theories of change and consistent implementation in gender-transformative intervention.


Assessment of endothelial function of the renal vasculature in human subjects.
L-Arginine, the substrate of nitric oxide (NO) synthase, and N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of endothelial NO synthase, are used to analyze endothelial function of the renal vasculature. However, little is known about the appropriate dose of L-arginine to be used and the duration of action of L-arginine and L-NMMA. Twenty-nine healthy male subjects (age, 27+/-1 years) were examined. In protocol 1 (N = 17), L-arginine at low (100 mg/kg) and high dose (250 mg/kg), and high-dose L-arginine combined either with L-NMMA (total dose, 4.25 mg/kg; N = 9) or placebo (N = 8) were given. In protocol 2 (N = 12), L-NMMA was given before L-arginine infusion (100 mg/kg). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured at rest and at the end of each infusion step. In protocol 1, L-arginine dose dependently increased RPF and GFR (RPF: 599+/-19 v 630+/-18 v 690+/-24 mL/min, P <.05; GFR: 111+/-3 v 115+/-3 v 121+/-3 mL/min, P <.01; for baseline, L-arginine 100 mg/kg and 250 mg/kg, respectively). However, these changes could not be antagonized by coinfusion of L-NMMA to L-arginine 250 mg/kg: RPF and GFR remained unchanged in both the placebo and the L-NMMA group. In protocol 2, L-NMMA decreased RPF (492+/-18 v 567+/-27 mL/min, P <.01) and increased GFR (122+/-4 v 118+/-3 mL/min, P <.05). These changes could only be partially reversed by subsequent infusion of L-arginine (RPF: 533+/-15 mL/min; GFR: 121+/-4 mL/min; both parameters P = NS v L-NMMA and v baseline). L-arginine at a dose of 100 mg/kg is sufficient to analyze endothelial function of the renal vasculature. The prolonged effect of L-NMMA and L-arginine must be taken into account in study protocols using both substances. Thus, stimulation and blockade of NO synthase cannot be examined in the same protocol.


Stem cell aging in the Drosophila ovary.
Accumulating evidence suggests that with time human stem cells may become defective or depleted, thereby contributing to aging and aging-related diseases. Drosophila provides a convenient model system in which to study stem cell aging. The adult Drosophila ovary contains two types of stem cells: the germ-line stem cells give rise to the oocyte and its supporting nurse cells, while the somatic stem cells give rise to the follicular epithelium-a highly differentiated tissue that surrounds each oocyte as it develops. Genetic and transgenic analyses have identified several conserved signaling pathways that function in the ovary to regulate stem cell maintenance, division and differentiation, including the wingless, hedgehog, JAK/STAT, insulin and TGF-β pathways. During Drosophila aging the division of the stem cells decreases dramatically, coincident with reduced egg production. It is unknown if this reproductive senescence is due to a defect in the stem cells themselves, or due to the lack of signals normally sent to the stem cells from elsewhere in the animal, such as from the central nervous system or the stem cell niche. Methods are being developed to genetically mark stem cells in adult Drosophila and measure their survival, division rate and function during aging.


Longitudinal impact of volunteering on the cognitive functioning of older adults: A secondary analysis from the US Health and Retirement Study.
To examine the relationship of volunteering with cognitive activity, social activity, and physical activity among older adults and, ultimately, with later cognitive functioning across different time periods. We used individual responding to three waves of the US Health and Retirement Study panel data from 2008, 2012, and 2016 (n = 2,862). Self-reported questionnaires were used to assess annual volunteering frequency (non volunteering, volunteering <100 h and ≥100 h), and an adapted version of the Telephone Interview for Cognitive Status (TICS) was used to assess memory, mental processing, knowledge, language, and orientation. A structural equation model was estimated to assess effects on cognitive functioning throughout waves. Those participants that were part of volunteering activities in 2012 showed an increase between 2008 and 2012 in moderate physical activity (β = 0.19, P < 0.001 for those volunteering less than 100 h and β = 0.21, P < 0.001 for those volunteering at least 100 h), increase in social activity (β = 0.10, P = 0.052 for those volunteering less than 100 h and β = 0.12, P = 0.018 for those volunteering at least 100 h) and increase in higher cognitive activity (β = 0.13, P < 0.001 for those volunteering at least 100 h), compared to participants who did not volunteer. Higher levels of cognitive activity in 2008 and 2012 were associated with higher cognitive functioning on the following waves (β = 0.66 and β = 0.60, P < 0.001, respectively). Volunteering is a modifiable activity that can be increased to bolster cognitive functioning in older adulthood, primarily mediated by increased cognitive activity.


Circumferential and longitudinal viscoelasticity of human iliac arterial segments in vitro.
A random noise technique was used to measure the circumferential and longitudinal dynamic elasticity of human common iliac arteries in vitro. For circumferential measurements the frequency ranged from 0.016 to 20 Hz; the phase lag of diameter behind pressure was found to be almost constant (about 5 degrees) and the Young's modulus of elasticity to increase rapidly at first and then more gradually beyond 1-2 Hz. Somewhat similar results were obtained for longitudinal elasticity. Arterial segments were found to be anisotropic when kept at in vivo length and under normal distending pressure.


Mechanistic target of rapamycin and an extracellular signaling-regulated kinases 1 and 2 signaling participate in the process of acetate regulating lipid metabolism and hormone-sensitive lipase expression.
Acetate plays an important role in host lipid metabolism. However, the network of acetate-regulated lipid metabolism remains unclear. Previous studies show that mitogen-activated protein kinases (MAPKs) and mechanistic target of rapamycin (mTOR) play a crucial role in lipid metabolism. We hypothesize that acetate could affect MAPKs and/or mTOR signaling and then regulate lipid metabolism. The present study investigated whether any cross talk occurs among MAPKs, mTOR and acetate in regulating lipid metabolism. The ceramide C6 (an extracellular signaling-regulated kinases 1 and 2 [ERK1/2] activator) and MHY1485 (a mTOR activator) were used to treat rabbit adipose-derived stem cells (ADSCs) with or without acetate, respectively. It indicated that acetate (9 mM) treatment for 48 h decreased the lipid deposition in rabbit ADSCs. Acetate treatment decreased significantly phosphorylated protein levels of ERK1/2 and mTOR but significantly increased mRNA level of hormone-sensitive lipase (HSL). Acetate treatment did not significantly alter the phosphorylated protein level of p38 MAPK and c-Jun aminoterminal kinase (JNK). Activation of ERK1/2 and mTOR by respective addition in media with ceramide C6 and MHY1485 significantly attenuated decreased lipid deposition and increased HSL expression caused by acetate. Our results suggest that ERK1/2 and mTOR signaling pathways are associated with acetate regulated HSL gene expression and lipid deposition.


Biomarkers as surrogate endpoints in cancer trials.
To define and discuss surrogate endpoint biomarkers, which are used in therapeutic trials as a substitute for the clinically meaningful "true" endpoint; and hence, may be used in answering cancer prevention questions in clinical trials evaluating drug/nutrient interventions for a number of common cancer sites. Literature, research articles. Surrogate endpoint biomarkers offer greater efficiency in clinical studies because they may allow for the generation of useful results from studies that are of shorter duration using smaller numbers of study participants in clinical trials for treatment and prevention of cancer. Continual changes in the science of cancer diagnosis and prevention demand rigorous scientific knowledge of the professional nurse to optimize the outcome of cancer prevention drug/agent development and the delivery of evidence-based care.


Challenges in screening for congenital hypothyroidism: Optimization of thyrotropin cut-off values.
Different protocols exist for newborn screening of congenital hypothyroidism (CH) worldwide, with different thyrotropin cut-off values for repetition and confirmation tests. This study aimed to assess local protocol in terms of specificity and improve our screening process by optimizing thyrotropin cut-off values. Subsequently, the cut-off values obtained were retrospectively applied to evaluate the number of tests avoided. Retrospective observational study between 2013 and 2019. All newborn children with a confirmation test for CH were considered for the study. ROC curve analysis was performed for thyrotropin cut-off value optimization in DBS which triggers a confirmatory test, and odds ratios were calculated. For individuals affected by the cut-off value modification, serum thyrotropin and free thyroxine in the confirmation test were analyzed for consideration of clinical outcomes. A total of 72,133 newborn children were screened for CH, and 208 individuals were included in the study. Incidence in our population was 1:2,000 live births. The area under the ROC curve was 0.819 (CI 95%: 0.748-0.897). While the current cut-off value (thyrotropin ≥ 10mIU/L) had a specificity of 31.8% [ORs: 3.5 (CI 95%: 1.4-8.8)], the optimal cut-off value (thyrotropin ≥ 15mIU/L) yielded a specificity of 92.4% for the detection of CH and transient hypothyroidism [ORs: 15.9 (CI 95%: 7.1-35.8)], with no loss of sensitivity. While keeping a maximum sensitivity, optimization of cut-off values may be of great use not only in management, but also in reducing family stress, which is of special relevance for the newborn.


Antibodies to glutaraldehyde-polymerized human albumin (anti-pHSA) in viral hepatitis.
The antibody to polymerized human albumin (anti-pHSA) was studied in normal subjects and in the course of infection from hepatitis A virus, hepatitis B virus, and hepatitis non-A, non-B virus. Results show that anti-pHSA antibody was never found in normal subjects, but it appeared during virus liver pathologies. The behavior of anti-pHSA differs in acute type A hepatitis that does not change to chronic form and in those forms which tend to become chronic (B and nonA, nonB). In the type-A infection anti-pHSA disappears after the acute phase; in the other two forms it persists all along as the infection develops. Specifically in non-A, non-B infection only the IgM type anti-pHSA is produced.


Determinants of Willingness to Undergo Lung Cancer Screening among High-Risk Current and Ex-smokers in Sabah, Malaysia: A Cross-Sectional Pilot Study.
Attitudes towards smoking, lung cancer screening, and perceived risk of lung cancer have not been widely studied in Malaysia. The primary objective of this study was to describe the factors affecting the willingness of high-risk current smokers and ex-smokers to undergo low-dose computed tomography (LDCT) screening for lung cancer. A prospective, cross-sectional questionnaire study was conducted in current smokers or ex-smokers aged between 55 and 80 years at three hospitals in Kota Kinabalu, Sabah, Malaysia. The questionnaire recorded the following parameters: perceived lung cancer risk; Prostate Lung Colon Ovarian Cancer 2012 risk prediction model excluding race and ethnicity predictor (PLCOm2012norace); demographic characteristics; psychosocial characteristics; and attitudes towards lung cancer and lung cancer screening. A vast majority of the 95 respondents (94.7%) indicated their willingness to undergo screening. Stigma of lung cancer, low levels of knowledge about lung cancer symptoms, concerns about financial constraints, and a preference for traditional medication were still prevalent among the respondents, and they may represent potential barriers to lung cancer screening uptake. A desire to have an early diagnosis (odds ratio [OR], 11.33; 95% confidence interval [CI], 1.53 to 84.05; p=0.02), perceived time constraints (OR, 3.94; 95% CI, 1.32 to 11.73; p=0.01), and proximity of LDCT screening facilities (OR, 14.33; 95% CI, 1.84 to 111.4; p=0.01) had significantly higher odds of willingness to undergo screening. Although high-risk current smokers and ex-smokers are likely to undergo screening for lung cancer, several psychosocial barriers persist. The results of this study may guide the policymakers and clinicians regarding the need to improve lung cancer awareness in our population.


1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP)-induced degeneration of mesostriatal dopaminergic neurons in the mouse: biochemical and neuroanatomical studies.
The neurotoxic effects of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), a substituted analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were studied in BALB/cJ mice. Moderate doses of 2'CH3-MPTP produced a greater depletion of dopamine (DA) in the striatum (45%) than in the nucleus accumbens (23%), and in these same animals, there was a 35% loss of midbrain DA neurons. The greatest loss of DA cells occurred within the substantia nigra (43%), and there was also a significant loss of cells within the ventral tegmental area (28%). Higher doses of 2'CH3-MPTP decreased levels of DA more in the axon terminal/forebrain region (72%) than in the cell body/midbrain region (25%). Similar forebrain/midbrain DA depletion ratios were also found in mice that received an electrolytic lesion of the midbrain DA neurons; there was a greater Da depletion in the forebrain (29%) than in the midbrain (8%). In both 2'CH3-MPTP and electrolytically lesioned animals there was a significant increase in DA turnover in the forebrain region, as measured by the homovanillic acid/DA ratio. These data indicate that 2'CH3-MPTP: (1) destroys DA neurons within two midbrain regions containing cells which project to the striatum (i.e. mesostriatal DA neurons), rather than just nigrostriatal DA neurons; (2) produces a greater loss of DA in the axon terminal region than in the cell body region; and (3) influences the mesostriatal DA neurons in the same way as does a lesion to the cell bodies. These data are discussed with regard to the pathophysiology of 2'CH3-MPTP.


Automated detection and analysis of foraging behavior in Caenorhabditis elegans.
Foraging is a rapid, side-to-side movement of the nose generated by Caenorhabditis elegans as it explores its environment. In this paper, we present an automated method to detect and analyze foraging behavior of C. elegans in a video sequence. Several morphological image-processing methods are used to locate the precise nose position of the worm in each image. Then foraging events are detected by measuring the bending angle of the nose and investigating the overall bending curve using periodograms. We measure foraging-related parameters which have not previously been studied. The algorithm has applications in classifying and characterizing genetic mutations associated with this behavior.


Tributyrate as a substrate for the determination of lipase activity in milk.
A procedure is described for the determination of the lipolytic activity in milk using tributyrate as substrate. The method is based on the titration of liberated butyric acid in a diethyl ether: light petroleum (2-75:1, v/v) extract of the incubation mixture. Some of the fundamental factors involved in the procedure are discussed.


Responsiveness of a patient in a persistent vegetative state after a coma to weekly injections of autologous activated immune cells: a case report.
An 82-year-old Caucasian woman had remained in a persistent vegetative state after a coma of seven months duration, which occurred after a stroke with hemiplegia, nine years previously. The persistent vegetative state could be reversed in part by weekly injections with activated immune cells. After therapy, our patient responded to commands in addition to regaining spontaneous movements of both arms and the ability to swallow. This is the first report on the treatment with activated immune cells of a patient in a persistent vegetative state after a coma. An 82-year-old Caucasian woman presented with a persistent vegetative state subsequent to a coma. She retained respiratory and autonomic functions. As contact was not possible, physiotherapy was passive. Her skin was yellowish, and our patient did not move by herself. Vomiting repeatedly resulted from tube feeding. After a once-weekly treatment with activated immune cells sampled from our patient's blood and activated in vitro, several of her functions gradually returned. Our patient opened her eyes in the requested direction and turned her head toward people entering the room. She 'supported' nursing efforts, as the nurse noted a loss of spastic motions. The strength in both her arms returned, and she spontaneously moved her arm on the side experiencing hemiplegia. After three months, our patient could stick out her tongue upon demand. Finally, the swallow reflexes of our patient started to return. However, tube feeding was continued, and our patient died after aspiration of vomit following a feeding. The success of treatment with autologous activated immune cells in this patient may have resulted from the production of neuroactive substances, such as neurotrophin-3 and brain-derived neurotrophic factor, by activated immune cells. The deterioration of our patient could be reversed, as demonstrated by the restoration of motor strength in her hemiplegic side. In addition, our patient was able to induce motor responses upon request. It seems reasonable to conclude that activated immune cells may improve the chronic vegetative state in some patients.


Correction: Kinchin, I.; Doran, C.M. The Cost of Youth Suicide in Australia. Int. J. Environ. Res. Public Health 2018, 15, 672.
The authors wish to add the following corrections to their paper published in the International Journal of Environmental Research and Public Health[...].


The influence of climate change on freshwater availability in the Sokoto Rima River Basin, Northwestern Nigeria.
This research entailed the acquisition of long-term (1980-2020) meteorological data (rainfall, temperature, and runoff) which was used to compute the values for the mean annual, monthly, and seasonal hydro-climate variables to establish their trend and behavior. To substantiate if the patterns of runoff are in any way due to the changing climate, the meteorological data were subjected to non-parametric tests-Mann-Kendall (MK), Sen's slope estimator, Kendall tau, and partial correlation. MK trend test for runoff, rainfall, and temperature (on an annual and seasonal basis) revealed significant trends on an annual scale. Nevertheless, rainfall data did not exhibit any, observable trend on a seasonal scale. On both annual and seasonal scales, temperature values showed increasing trends. In the entire period considered (1980-2020), runoff also exhibited a remarkable increase in trend. Sen's estimator values ranged from - 0.04 to 3.23. The results of the Kendall tau correlation showed that runoff is positively correlated to rainfall (tau = 0.222), with a high confidence level (95%). Again, the partial correlation analysis of runoff and climatic variables for annual and seasonal timescale, results show that the runoff is significantly (rxy.z = 0.315) affected by both rainfall and temperature. It is therefore recommended that future research should utilize robust input-output models to determine the amount of water stress in the basin. As a sustainable management approach, artificial surface water reservoirs should be constructed to complement the available water from the Sokoto-Rima river and alleviate the water stress experienced by the population.


Quantification and handling of nonlinearity in Raman micro-spectrometry of pharmaceuticals.
This work demonstrates how nonlinearity in Raman spectrometry of pharmaceuticals can be handled and accurate quantification can be achieved by applying certain chemometric methods including variable selection. Such approach proved to be successful even if the component spectra are very similar or spectral intensities of the constituents are strongly different. The relevant examples are: blends of two crystalline forms of carvedilol ("CRYST-PM" blend) and a three-component pharmaceutical model system ("PHARM-TM" blend). The widely used classical least squares regression (CLS) and partial least squares regression (PLS) quantification methods provided relatively poor root mean squared error of prediction (RMSEP) values: approximately 2-4% and 4-10% for CRYST-PM and PHARM-TM respectively. The residual plots of these models indicated the nonlinearity of the preprocessed data sets. More accurate quantitative results could be achieved with properly applied variable selection methods. It was observed that variable selection methods discarded the most intensive bands while less intensive ones were retained as the most informative spectral ranges. As a result not only the accuracy of concentration determination was enhanced, but the linearity of models was improved as well. This indicated that nonlinearity occurred especially at the intensive spectral bands. Other methods developed for handling nonlinearity were also capable of adapting to the spectral nature of both data sets. The RMSEP could be decreased this way to 1% in CRYST-PM and 3-6% in PHARM-TM. Raman maps with accurate real concentrations could be prepared this way. All quantitative models were compared by the non-parametric sum of ranking differences (SRD) method, which also proved that models based on variable selection or nonlinear methods provide better quantification.


Uterine smooth muscle tumors of uncertain malignant potential: diagnostic challenges and therapeutic dilemmas. Report of 2 cases and review of the literature.
Morphologically, there exist variants of uterine smooth muscle tumors that cannot be clearly interpreted and classified as benign or malignant. Because their behavior and clinical prognosis is also uncertain, the World Health Organization has termed these "smooth muscle tumors of uncertain malignant potential" (STUMP). Herein we describe 2 cases, present a review of the literature, and highlight the diagnostic challenges and therapeutic dilemmas associated with uterine STUMP in myomectomy specimens from women who wish to maintain or enhance their fertility. The clinical course of residual STUMP remains speculative.


Eucannabinolide, a novel sesquiterpene lactone, suppresses the growth, metastasis and BCSCS-like traits of TNBC via inactivation of STAT3.
Signal transducer and activator of transcription 3 (STAT3) is an important therapeutic target to triple negative breast cancer (TNBC) treatment. In the present study, we aim to investigate the potential activity of Eucannabinolide (Euc), a novel sesquiterpene lactone separated from Eupatorium cannabinum Linn. against TNBC by targeting STAT3 and expect that Euc will be developed as an inhibitor of STAT3 in the treatment of TNBC. We found that Euc effectively suppressed STAT3 activation at tyrosine 705, inhibited its translocation to nucleus, and decreased its DNA binding capacity. Moreover, introduction of STAT3-short hairpin RNAs or STAT3 inhibitor S3I-201 attenuates the Euc-induced inhibition of cell viability. And, Euc inhibited cell viability, proliferation, metastasis and breast cancer stem cell-like traits but did not induce cytotoxicity in human mammary epithelial cells. The in vivo study similarly demonstrated that administration of Euc inhibited the growth of xenograft tumors and impaired tumor metastasis of a lung metastasis model. The above phenomena were associated with STAT3 dysfunction induced by Euc. In conclusion, Euc elicits the effects of anti-proliferation, anti-metastasis and anti-breast cancer stem cell-like traits in TNBC via targeting STAT3. These data highlight that development of Euc as a STAT3 inhibitor may offer a promising therapeutic strategy for TNBC.


Development and optimization of a LC-MS based multi-attribute method (MAM) workflow for characterization of therapeutic Fc-fusion protein.
The growing complexity of novel biopharmaceutical formats, such as Fc-fusion proteins, in increasingly competitive environment has highlighted the need of high-throughput analytical platforms. Multi-attribute method (MAM) is an emerging analytical technology that utilizes liquid chromatography coupled with mass spectrometry to monitor critical quality attributes (CQAs) in biopharmaceuticals. MAM is intended to supplement or replace the conventional chromatographic and electrophoretic approaches used for quality control and drug release purpose. In this investigation, we have developed an agile sample preparation approach for deploying MAM workflow for a complex VEGFR-targeted therapeutic Fc-fusion protein. Initially, a systematic time course evaluation of tryptic digestion step was performed to achieve maximum amino acid sequence coverage of >96.5%, in a short duration of 2 h, with minimum assay artifacts. This approach facilitated precise identification of five sites of N-glycosylation with successful monitoring of other CQAs such as deamidation, oxidation, etc. Subsequently, the developed MAM workflow with suitable tryptic digestion time was qualified according to the International council for harmonisation (i.e. ICH) Q2R1 guidelines for method validation. Post-validation, the analytical workflow was also evaluated for its capability to identify unknown moieties, termed as 'New Peak Detection' (i.e. NPD), and assess fold change between the reference and non-reference samples, in a representative investigation of pH stress study. The study, thus, demonstrated the suitability of the MAM workflow for characterization of heavily glycosylated Fc-fusion proteins. Moreover, its NPD feature could offer an all-encompassing view if applied for forced degradation and stability studies.


Plasma antioxidants and asymptomatic carotid atherosclerotic disease.
Atherosclerosis remains clinically mute for a long time and frequently manifests itself with an acute cardiovascular event. The possibility of detecting this disease in a subclinical phase and reducing or reversing its progression is an issue of relevance. Published studies on the association between antioxidant vitamins and carotenoids and carotid intima-media thickness (CIMT) have been inconclusive. We enrolled 220 consecutive, asymptomatic participants. After carotid ultrasound investigation, a medical history was taken, a physical examination was performed and venous blood samples were collected. Venous blood samples were analyzed for concentrations of antioxidant vitamins and carotenoids. Low concentrations of vitamin A (p < 0.01), vitamin E (p < 0.001), lycopene (p < 0.01) and beta-carotene (p < 0.001) were significantly associated with carotid atherosclerosis (CIMT > or = 0.8 mm). In addition, marginally higher body mass index, plasma haemoglobin and high-density lipoprotein cholesterol were also associated with carotid atherosclerosis, while other laboratory parameters considered in this study (total cholesterol, low-density lipoprotein cholesterol, triglycerides and C-reactive protein) were not significantly associated with carotid atherosclerosis. Low plasma concentrations of antioxidant vitamins (A, E, beta-carotene) and lycopene were associated with early carotid atherosclerotic lesions as measured by CIMT. Regular intake of foods rich in lycopene and antioxidant vitamins may slow the progression of atherosclerosis.


Autism-like behaviors in male mice with a Pcdh19 deletion.
Mutations in protocadherin 19 (PCDH19), which is on the X-chromosome, cause the brain disease Epilepsy in Females with Mental Retardation (EFMR). EFMR is also often associated with autism-like symptoms. In mice and humans, epilepsy occurs only in heterozygous females who have a mixture of PCDH19 wild-type (WT) and mutant cells caused by random X-inactivation; it does not occur in hemizygous PCDH19 mutant males. This unique inheritance pattern strongly suggests the underlying disease mechanism operates via interference between WT and mutant cells rather than being a result of complete loss of PCDH19 functions. Although it remains unclear whether the other symptoms of EFMR also conform to this unique genotype-phenotype relationship, PCDH19 mutant males were recently reported to demonstrate autism-like symptoms. We, therefore, used a Pcdh19 knockout (KO) mouse model to ask whether a complete lack of PCDH19 causes autism-like behaviors. Consistent with the autism observed in EFMR females, we found Pcdh19 heterozygous KO female mice (with mosaic expression of PCDH19) show defects in sociability in the 3-chamber test. Surprisingly, hemizygous Pcdh19 KO male mice (without any PCDH19 expression) exhibit impaired sociability in the 3-chamber test and reduced social interactions in the reciprocal social interaction test. We also observed that, compared to WT mice, mutant mice display more repetitive behaviors, including self-grooming and rearing. These findings indicate that hemizygous Pcdh19 KO male mice show autism-like phenotypes.


Clinical pharmacokinetics of commonly used anticancer drugs.
The quantitative aspects of drug disposition in man of the commonly used antineoplastic agents, including cyclophosphamide, the nitrosoureas, cisplatin, methotrexate, cytarabine, 5-fluorouracil, doxorubicin, daunorubicin, bleomycin, vincristine, vinblastine, and vindesine are reviewed. Although the pharmacokinetic behaviour of these drugs has been adequately described in man, the chemical reactivity, the complexity of metabolism and disposition, the lack of simple, rapid and sensitive assays to measure plasma concentration, and the lack of defined therapeutic and toxic plasma concentrations have limited the application of routine drug monitoring in clinical oncology. With the exception of high dose methotrexate, drug doses and administration schedules remain empirical with a standard starting dose and subsequent dosage modifications determined by ensuing drug toxicities. However, many of the pharmacological characteristics of the drugs, such as their low therapeutic index, potentially life-threatening toxicities and wide individual variability in drug disposition, necessitate pharmacological monitoring. Comprehensive pharmacokinetic analysis of new and established antineoplastic agents does play a role in defining dosage, administration schedule, route of administration, and dosage modification in the presence of organ dysfunction. Consideration of the kinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.


A systematic approach to the disclosure of genomic findings in clinical practice and research: a proposed framework with colored matrix and decision-making pathways.
Whether and how to disclose genomic findings obtained in the course of genomic clinical practice and medical research has been a controversial global bioethical issue over the past two decades. Although several recommendations and judgment tools for the disclosure of genomic findings have been proposed, none are sufficiently systematic or inclusive or even consistent with each other. In order to approach the disclosure/non-disclosure practice in an ethical manner, optimal and easy-to-use tools for supporting the judgment of physicians/researchers in genomic medicine are necessary. The bioethics literature on this topic was analyzed to parse and deconstruct the somewhat overlapping and therefore ill-defined key concepts of genomic findings, such as incidental, primary, secondary, and other findings. Based on the deconstruction and conceptual analyses of these findings, we then defined key parameters from which to identify the strength of duty to disclose (SDD) for a genomic finding. These analyses were then applied to develop a framework with the SDD matrix and systematic decision-making pathways for the disclosure of genomic findings. The following six major parameters (axes), along with sub-axes, were identified: Axis 1 (settings and institutions where findings emerge); Axis 2 (presence or absence of intention and anticipatability in discovery); Axis 3 (maximal actionability at the time of discovery); Axis 4 (net medical importance); Axis 5 (expertise of treating physician/researcher); and Axis 6 (preferences of individual patients/research subjects for disclosure). For Axes 1 to 4, a colored SDD matrix for genomic findings was developed in which levels of obligation for disclosing a finding can be categorized. For Axes 5 and 6, systematic decision-making pathways were developed via the SDD matrix. We analyzed the SDD of genomic findings and developed subsequent systematic decision-making pathways of whether and how to disclose genomic findings to patients/research subjects and their relatives in an ethical manner. Our comprehensive framework may help physicians and researchers in genomic medicine make consistent ethical judgments regarding the disclosure of genomic findings.


Circulating lymphocyte subsets in human acute pancreatitis.
We investigated peripheral lymphocyte subsets in 34 consecutive acute pancreatitis patients (21 males, 13 females; mean age, 57 years; range, 16-85 years) studied within 48 h of pain onset and for 5 consecutive days to understand better the immunological response during the course of the disease. The diagnosis was based on characteristic abdominal pain associated with a twofold increase in serum lipase and confirmed by imaging techniques in all patients. Acute pancreatitis was of biliary origin in 25 patients, due to alcohol abuse in 5, due to pancreas divisum in 1, and of unknown origin in 3. Fifteen patients had severe illness and 19 had mild disease. In all patients, total lymphocyte and lymphocyte subset counts were carried out on admission, as well as on the third and fifth day of hospitalization, using a flow cytometric analysis. Twenty-three patients (13 with severe illness and 10 with mild disease) also had a repeat count 1 month after recovery. Twenty-five healthy subjects and 27 patients with nonpancreatic acute abdomen comparable for sex and age were studied as controls. On the first day of the study, the leukocyte number was significantly higher in patients with acute pancreatitis and in those with nonpancreatic acute abdomen with respect to healthy subjects, whereas the number of total and CD4+, CD8+, CD3+ DR-, and CD3- DR+ lymphocytes was significantly lower in acute pancreatitis patients than in healthy subjects or in patients with nonpancreatic acute abdomen. These subject counts persisted on the third and fifth days of the study.(ABSTRACT TRUNCATED AT 250 WORDS)


A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation.
Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal's first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.


RNA silencing suppressor p21 of Beet yellows virus forms an RNA binding octameric ring structure.
Many plant viruses encode proteins that suppress the antiviral RNA silencing response mounted by the host. The suppressors p19 from tombusvirus and p21 from Beet yellows virus appear to block silencing by directly binding siRNA, a critical mediator in the process. Here, we report the crystal structure of p21, which reveals an octameric ring architecture with a large central cavity of approximately 90 A diameter. The all alpha-helical p21 monomer consists of N- and C-terminal domains that associate with their neighboring counterparts through symmetric head-to-head and tail-to-tail interactions. A putative RNA binding surface is identified in the conserved, positive-charged inner surface of the ring. In contrast to the specific p19-siRNA duplex interaction, p21 is a general nucleic acid binding protein, interacting with 21 nt or longer single- and double-stranded RNAs in vitro. This study reveals an RNA binding structure adopted by the p21 silencing suppressor.


Oral administration of Flavonifractor plautii attenuates inflammatory responses in obese adipose tissue.
Adipose tissue inflammation enhances the symptoms of metabolic syndrome. Flavonifractor plautii, a bacterium present in human feces, has been reported to participate in the metabolism of catechin in the gut. The precise function of F. plautii remains unclear. We assessed the immunoregulatory function of F. plautii both in vitro and in vivo. In vitro, we showed that both viable and heat-killed F. plautii attenuated TNF-α transcript accumulation in lipopolysaccharide-stimulated RAW 264.7 cells. For the in vivo experiment, male C57BL/6 were placed on a high-fat diet (HFD) for 11 weeks. During the final two weeks on the HFD, the animals were administered with F. plautii by once-daily oral gavage. The oral administration of F. plautii attenuated the increase in TNF-α transcription otherwise seen in the epididymal adipose tissue of HFD-fed obese mice (HFD + F. plautii). The composition of the microbial population (at the genus level) in the cecal contents of the HFD + F. plautii mice was altered considerably. In particular, the level of Sphingobium was decreased significantly, and that of Lachnospiraceae was increased significantly, in the HFD + F. plautii group. Obesity is closely associated with the development of inflammation in adipose tissue. F. plautii may be involved in inhibition of TNF-α expression in inflammatory environments. Our results demonstrated that F. plautii may be useful for alleviating the inflammatory responses of adipose tissue.


Transbronchial biopsy using endobronchial ultrasonography with a guide sheath and virtual bronchoscopic navigation.
We evaluated the feasibility, safety, and efficacy of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) and virtual bronchoscopy (VB) navigation for small peripheral pulmonary lesions < or = 30 mm in diameter. Pilot study. A national university hospital. We performed TBB using EBUS-GS with VB navigation for 29 patients with 30 small peripheral pulmonary lesions (average diameter, 18.6 mm) between January 1, 2004, and August 31, 2004. VB images were reconstructed from helical CT data. TBB was then performed using EBUS-GS with VB navigation. In all patients, TBB was performed safely with no complications. Bronchi seen on VB imaging were highly consistent with the actual structures confirmed using fiberoptic bronchoscopy. Following VB navigation, the endobronchial ultrasonography (EBUS) probe was inserted into third- to sixth-generation bronchi. Twenty-four lesions (80%) were visualized on EBUS images. Average durations of the initial EBUS examination of lesions, first biopsy, and the total procedure were 9.56 min, 11.99 min, and 25.72 min, respectively. Nineteen lesions (63.3%) were diagnosed from histopathologic or cytologic examination. Diagnostic sensitivities were 44.4% (8 of 18) for lesions < 20 mm in mean diameter and 91.7% (11 of 12) for lesions 20 to 30 mm in mean diameter. In summary, TBB using EBUS-GS with VB navigation was safely performed and was effective in diagnosing small peripheral pulmonary lesions.


Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles.
It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://forensic.ugent.be/FLAD/. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://forensic.ugent.be/FLAD/ and add loci and allele sequences with a short and simple application interface (API).


The interval between a single course of antenatal steroids and delivery and its association with neonatal outcomes.
This study was undertaken to determine whether the benefits of a single course of antenatal steroid treatment for neonatal respiratory morbidity diminish beyond 7 days. A retrospective chart review was performed of all deliveries less than 34 weeks' gestation where delivery occurred after completing a single course of antenatal steroids (dexamethasone or betamethasone). Maternal and neonatal charts were reviewed, treatment course was confirmed, and neonatal morbidities were collected. Of 197 neonates whose mothers received a full course of antenatal steroids, 98 delivered within 7 days and 99 delivered more than 7 days after the initial dose. The 2 groups were similar in gestational age at delivery (30 weeks 0 days vs 30 weeks 4 days). The groups were also similar in maternal age, race, payor status, type of steroid given, route of delivery, gender, and birth weight. Overall, infants delivering within 7 days had a lower incidence of receiving respiratory support for more than 24 hours (62% vs 81%, P < .01), but there were no significant differences between the groups in surfactant treatment (39% vs 47%), use of mechanical ventilation (49% vs 59%), necrotizing enterocolitis (6% vs 4%), intraventricular hemorrhage (15% vs 20%), oxygen dependence at 28 days (24% vs 23%) or at 36 weeks estimated gestational age (13% vs 12%), length of stay (34 days vs 38 days), or mortality (2 vs 0). These results were no different when evaluating only infants delivered before 30 weeks. Among infants exposed to a single course of antenatal steroids, delivering more than 7 days after initiation of treatment was associated with an increased need for short-term respiratory support, but not other measures of neonatal morbidity. These data challenge the concept of diminishing efficacy of steroids after 7 days, and question the need for considering a rescue course.


Cardiovascular benefits of GLP-1RA and SGLT-2i in women with type 2 diabetes.
Given the CV benefit noted in the CVOTs, GLP-1RAs and SGLT-2is are given preference in T2DM guidelines. While guidelines do not report potential gender difference, those differences exist. On restricting the CVOTs results to women with increased CV risk or established ASCVD, GLP-1RAs significantly reduced MACE while SGLT-2is resulted in a non-significant reduction.


Phosphoinositides and Charcot-Marie-tooth disease: new keys to old questions.
Recent research into the genetic basis and the molecular disease mechanisms of Charcot-Marie-Tooth disease (CMT), also called hereditary motor and sensory neuropathies, has highlighted phosphoinositides, membrane-tethered phosphorylated metabolites of phosphatidylinositol, as key regulatory molecules in peripheral nerves in health and disease. Enzymes that dephosphorylate the endosomal phosphoinositides phosphatidylinositol-3-phosphate and/or phosphatidylinositol-3,5-biphosphate, and proteins with binding domains for these phosphoinositides, are mutated in subtypes of CMT. A hypothetical picture emerges suggesting that the precise regulation of phosphoinositide levels within neural cells, a process in turn critical for the correct dynamics of proteins binding to phosphoinositides, is a crucial bottleneck for the accurate function of myelinated peripheral nerves in both neurons and Schwann cells. The underlying molecular and cellular mechanisms are largely unknown. Some hypotheses are discussed in this essay.


Computational algorithmic and molecular dynamics study of functional and structural impacts of non-synonymous single nucleotide polymorphisms in human DHFR gene.
Human dihydrofolate reductase (DHFR) is a conserved enzyme that is central to folate metabolism and is widely targeted in pathogenic diseases as well as cancers. Although studies have reported the fact that genetic mutations in DHFR leads to a rare autosomal recessive inborn error of folate metabolism and drug resistance, there is a lack of an extensive study on how the deleterious non-synonymous SNPs (nsSNPs) disrupt its phenotypic effects. In this study, we aim at discovering the structural and functional consequences of nsSNPs in DHFR by employing a combined computational approach consisting of ten recently developed in silico tools for identification of damaging nsSNPs and molecular dynamics (MD) simulation for getting deeper insights into the magnitudes of damaging effects. Our study revealed the presence of 12 most deleterious nsSNPs affecting the native phenotypic effects, with three (R71T, G118D, Y122D) identified in the co-factor and ligand binding active sites. MD simulations also suggested that these three SNPs particularly Y122D, alter the overall structural flexibility and dynamics of the native DHFR protein which can provide more understandings into the crucial roles of these mutants in influencing the loss of DHFR function.


[Results of displacement studies on benzodiazepine receptors (123I-iomazenil and flumazenil)].
SPECT studies with 123I-iomazenil were performed in 14 patients with hepatic encephalopathy. The activity concentration in the brain decreases spontaneously by 10 to 20% within 80 min, in the nasal tissue by 35%. After an i.v. injection of 0.1 to 0.5 mg flumazenil a decrease of 29 to 38% is observed within 20 min, with a comparable decrease in white matter and nasal tissue. The application of well-known models of receptor kinetics is therefore impossible.


Spontaneous pain in partial nerve injury models of neuropathy and the role of nociceptive sensory cover.
Spontaneous pain is difficult to measure in animals. One proposed biomarker of spontaneous pain is autotomy, a behavior frequently observed in rats with complete hindpaw denervation (the neuroma model of neuropathic pain). A large body of evidence suggests that this behavior reflects spontaneous dysesthesic sensations akin to phantom limb pain or anesthesia dolorosa. After partial paw denervation, such as in the spared nerve injury (SNI) model of neuropathic pain, autotomy is rare. Does this mean that spontaneous pain is absent? We denervated hindpaws in two stages: SNI surgery completed 7 or 28 days later by transection of the saphenous and sural nerves (SaSu). Minimal autotomy was evoked by the first stage. But it started rapidly after SaSu surgery rendered the limb numb, much more rapidly than after denervation in a single stage (neuroma model). The acceleration was proportional to the delay between the two surgeries. This "priming" effect of the first surgery indicates that the neural substrate of autotomy, spontaneous neuropathic pain, was not initiated by the onset of numbness, but rather by the first, SNI surgery. But the animal's pain experience was occult. The saphenous and sural nerves provided nociceptive sensory cover for the paw, preventing the behavioral expression of the spontaneous pain in the form of autotomy. The results support prior observations suggesting that partial nerve injury triggers spontaneous pain as well as allodynia, and illustrate the importance of nociceptive sensory cover in the prevention of self-inflicted limb injury.


Augmented expression of macrophage migration inhibitory factor (MIF) in the telencephalon of the developing rat brain.
Macrophage migration inhibitory factor (MIF) has been characterized as a proinflammatory cytokine, hormone, and immunomodulator. We previously demonstrated the distribution of MIF in the adult rat brain and revealed its expression in neurons as well as glial cells. In this study, we investigated the localization of MIF in the developing rat brain from embryonic day (ED) 13 to ED19, and after birth from postnatal day (PD) 1 to PD28 using both immunohistochemistry and in situ hybridization. On ED16, the signals of MIF mRNA were high in the ventricular, subventricular, and intermediate zones of the telencephalon, in which 'neuropoietic' progenitor cells proliferate and migrate from the ventricular zone to the superficial layer in the cerebral cortex. The mRNA expression was detected throughout the postnatal period, and intense signals of the transcript were seen in the ventricle and in layers I, II and III of the cerebral cortex at PD5. Similarly, positive staining of MIF protein was seen in the ventricular zone by immunohistochemical analysis, although the positively stained area appeared to be smaller than the mRNA expression. Taken together, these results suggest that the increase in MIF mRNA in the developing brain reflects the growth and maturation of neurons and glial cells.


Application of electronic nose for industrial odors and gaseous emissions measurement and monitoring--An overview.
The present review evaluates the key modules of the electronic nose, a biomimetic system, with specific examples of applications to industrial emissions monitoring and measurement. Regulations concerning the odor control are becoming very strict, due to ever mounting environmental pollution and its subsequent consequences and it is advantageous to employ real time measurement system. In this perspective, systems like the electronic nose are an improved substitute for assessing the complex industrial emissions over other analytical techniques (odorant concentration measurement) and olfactometry (odor concentration measurement). Compared to tools like gas chromatography, electronic nose systems are easy to develop, are non-destructive and useful for both laboratory and on field purposes. Although there has been immense development of more sensitive and selective sensor arrays and advanced data mining techniques, there have been limited reports on the application of electronic nose for the measurement of industrial emissions. The current study sheds light on the practical applicability of electronic nose for the effective industrial odor and gaseous emissions measurement. The applications categorization is based on gaseous pollutants released from the industries. Calibration and calibration transfer methodologies have been discussed to enhance the applicability of electronic nose system. Further, industrial gas grab sampling technique is reviewed. Lastly, the electronic mucosa system, which has the ability to overcome the flaws of electronic nose system, has been examined. The review ends with the concluding remarks describing the pros and cons of artificial olfaction technique for the industrial applications.


1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulating IDO expression and re-activating immune cells function.
The indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl-tryptophan (1-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors by inhibiting tumor immune escape. A greater understanding of IDO activity is required to begin to understand the molecular mechanism by which drugs work. This study was conducted to investigate of the clinical significance of 1-methyl-tryptophan (1-MT) in treating carboplatin-resistant (CBP-resistant) ovarian cancer and its mechanism of action. Using a medium dose, intermittent treatment method, a clinically relevant CBP-resistant human ovarian cancer cell line (SKOV3/CBP) was established. SKOV3/CBP cells were treated with normal serum (control) or 1-MT (0.25 ng/mL) for 4 h (SKOV3/CBP + 1-MT). Cell proliferation, invasion and IDO expression in SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by MTT assays, Matrigel invasion chambers assays and ELISAs, respectively. The half-maximal inhibitory concentration (IC50) and resistance index (RI) were also calculated. The killing ability of the NK cells and CD8+ T cells co-cultured with SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by LDH activity assays and the INF-γcounting method. The SKOV3/CBP cell line displayed an increased IC50 compared to the SKOV3 cell line (P < 0.05) under CBP treatment. Treatment with 1-MT significantly decreased the IC50 and RI of SKOV3/CBP cells. Furthermore, 1-MT treatment not only reduced the invasion ability, but also suppressed IDO expression in the drug-resistant SKOV3/CBP + 1-MT cell line as compared to the SKOV3/CBP cell line. Furthermore, 1-MT enhanced the killing ability of NK cells and the amount of INF-γsecreted from CD8+ T cells which were co-cultured with the SKOV3/CBP cell line. Our data suggested that 1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulation of IDO expression which leads to re-activation of immune cell function. We provide a conceptual foundation for the clinical development of 1-MT as an anti-tumor immunomodulator for chemotherapy resistant ovarian cancer patients.


An obligatory role of protein glycosylation in the life cycle of yeast cells.
In the presence of 2-4 micrograms tunicamycin/ml, yeast cells stop growth after the cell number has increased 1.5-1.7-fold. The cells are arrested in G1: the rate of DNA synthesis greatly decreases and the budding index drops from 0.6 to 0.1 RNA synthesis is inhibited concomitantly, whereas protein synthesis is little affected. It is postulated that for G1/S phase transition to occur one or more proteins have to be glycosylated.


Cumulative Payments Through the Earned Income Tax Credit Program in Childhood and Criminal Conviction During Adolescence in the US.
Childhood poverty is associated with poor health and behavioral outcomes. The Earned Income Tax Credit (EITC), first implemented in 1975, is the largest cash transfer program for working families with low income in the US. To assess whether cumulative EITC payments received during childhood are associated with the risk of criminal conviction during adolescence. In this cohort study, the analytic sample consisted of US children enrolled in the 1979 National Longitudinal Study of Youth. The children were born between 1979 and 1998 and were interviewed as adolescents (age 15-19 years) between 1994 and 2016. Data analyses were performed from May 2021 to September 2022. Cumulative simulated EITC received by the individual's family from birth through age 14 years. The main outcome was dichotomous, self-reported conviction for a crime during adolescence (age 14-18 years). A cumulative, simulated measure of mean EITC benefits received by a child's family from birth through age 14 years was derived from federal, state, and family-size differences in EITC eligibility and payments during the study period to capture EITC benefit variation due to differences in policy parameters but not endogenous factors such as changes in household income. Logistic regression models with fixed effects for state and year and robust SEs clustered by mother estimated relative risk of adolescent conviction. Models were adjusted for state-, mother-, and child-level covariates. The analytical sample consisted of 5492 adolescents born between 1979 and 1998; 2762 (50.3%) were male, 1648 (30.0%) were Black, 1125 (20.5%) were Hispanic, and 2719 (49.5%) were not Black or Hispanic. Each additional $1000 of EITC received during childhood was associated with an 11% lower risk of self-reported criminal conviction during adolescence (adjusted odds ratio, 0.89; 95% CI, 0.84-0.95). Adjusted risk differences were larger among boys (-14.2 self-reported convictions per 1000 population [95% CI, -22.0 to -6.3 per 1000 population]) than among girls (-6.2 per 1000 population [95% CI, -10.7 to -1.6 per 1000 population]). The findings suggest that income support from the EITC may be associated with reduced youth involvement with the criminal justice system in the US. Cost-benefit analyses of the EITC should consider these longer-term and indirect outcomes.


Injuries to children caused by burning rice husk.
A case study of injury to the feet of children from Sri Lanka due to burning husk is discussed. The hot husk causes deep burns on the dorsum of the feet and spares the plantar surface. The contractures caused by the burns lead to severe deformity, and are very resistant to treatment. These burn injuries need to be treated early, in specialized centers, to avoid long term complications. Health education of the public plays an important role in the prevention of these injuries.


Supportive therapies in the prevention of chemotherapy-induced febrile neutropenia and appropriate use of granulocyte colony-stimulating factors: a Delphi consensus statement.
Data indicate that the use of prophylactic granulocyte colony-stimulating factors (G-CSFs) for chemotherapy-induced febrile neutropenia (FN) in routine practice is not consistent with guideline recommendations. The initiative "supportive care for febrile neutropenia prevention and appropriateness of G-CFS use" was undertaken to address the issue of inappropriate prescription of G-CSFs and to improve guideline adherence in the treatment of FN. In a two-round Delphi procedure, 36 medical oncologists reviewed clinically relevant recommendations on risk assessment, the appropriate use of G-CSFs, and the prevention of FN based on available literature and individual clinical expertise. The consensus was reached on 16 out of 38 recommendations, which are backed by evidence from randomised clinical trials and routine clinical practice. The medical oncologists agreed that the severity of neutropenia depends on patients' characteristics and chemotherapy intensity, and therefore, the risk of severe neutropenia or FN should be assessed at each chemotherapy cycle so as to initiate prophylaxis with G-CSFs if required. The use of biosimilar G-CSFs, with similar efficacy and safety profiles to the originator biologic, has improved the availability and sustainability of cancer care. The timing of supportive therapy is crucial; for example, long-acting G-CSF should be administered 24-72 h after chemotherapy administration. Each biological agent has a recommended administration dose and duration, and it is important to follow these recommendations to avoid complications associated with under-prophylaxis. It is hoped that these statements will help to increase adherence to guideline recommendations for appropriate G-CSF use and improve patient care.


Inverting a Laplacian topography map.
There are some occasions when it is better to use the Laplacian of the scalp voltages (e.g., for topographic displays and dipole source localization) and other occasions when it is better to use the original voltages (e.g., for comparison to non-Laplacian topography maps). This paper presents a simple algorithm for going between these two representations of the data. The inverse Laplacian involves iterative feedback. An Excel spreadsheet implementation of the algorithm is presented.


Bacillus thuringiensis cry toxin triggers autophagy activity that may enhance cell death.
Although it is well known that Bacillus thuringiensis Cry toxins kill insect pest by disrupting midgut cells of susceptible larvae through their pore formation activity, it is not clear what intracellular events are triggered after pore formation on the cell membrane of the target cells. Here we analyzed the role of Cry toxins on autophagy activation using several cell lines as models as well as in Helicoverpa armigera larvae. The selected insect cell lines (Hi5, Sl-HP and Sf9) were susceptible to activated Cry1Ca toxin, but only Sl-HP cells were also susceptible to activated Cry1Ac toxin. In contrast, the mammalian cell line 293 T was not susceptible to Cry1Ac or to Cry1Ca. Results show that Cry toxins induced autophagy only in the susceptible cell lines as shown by the analysis of the changes in the ratio of Atg8-PE to Atg8 and by formation of autophagosome dots containing Atg8-PE. The Cry1Ac enhanced autophagy in the midgut tissue of H. armigera larvae. Silencing expression of specific genes by RNAi assays confirmed that the autophagy induced by activated Cry toxins was dependent on AMPK and JNK pathways. Finally, inhibition of autophagy in the cell lines by specific inhibitors or RNAi assays resulted in delayed cell death triggered by Cry toxins, suggesting that the increased autophagy activity observed after toxin intoxication may contribute to cell death.


Endoscopic Treatment of Intussusception From Massive Colonic Lipomas via Endoscopic Mucosal Resection: A Case Series.
Although the safety and effectiveness of endoscopic resection of colonic lipomas has already been described, the ideal excisional technique continues to be debated. Notably, a majority of the proposed techniques focus on small, incidentally found lipomas. We report 3 patients with massive (≥8 cm) colonic lipomas presenting as intussusception that were successfully treated by piecemeal endoscopic mucosal resection. We propose endoscopic mucosal resection as the endoscopic treatment of choice and feasible alternative to surgery for the management of intussuscepting lipomas.


Pressure-gated capillary nanovalves based on liquid nanofilms.
Nanoscale valving is essential to expand the potentiality of the nanodevices. However, it is difficult to fabricate valves with movable control elements in nanoscale systems and thus it is desirable to design a nanovalve which can manipulate opening and blocking a gate without moving parts. A pressure-gated capillary valve which contains a nanoscale liquid layer sandwiched between two plates with two aligned orifices was designed and the proof-of-concept demonstration was achieved by Many-body Dissipative Particle Dynamics. The concave or convex meniscus appears naturally within the orifice of the capillary valve and can be controlled by the pressure difference between liquid and gas phases based on Young-Laplace equation and the edge effect. The closed state can be transformed into the open state (hole) when the two concave menisci are allowed to touch each other. The on/off switch is reversible by Laplace pressure manipulation and the passing and blocking of the fluid particles through the valve is verified.


Role of DNA dynamics in Alzheimer's disease.
DNA is a dynamic molecule, the conformation of which plays a major role in biological function. The non-B-form of DNA conformations are reported in the patho-physiology of diseases like Fragile X-syndrome, Huntington's chorea, Alzheimer's and others. Recently, our laboratory discovered the presence of Z-DNA in the hippocampal region of severely affected Alzheimer's disease (AD) brain samples. Alternate purine-pyrimidine bases, potential sequences adopting Z-DNA, are present in the promoter regions of AD specific genes like amyloid precursor protein (APP), Presenilin and ApoE. Thus, Z-DNA might be involved in the expression of these pathologically important genes. In the present review, we have focused on the possible mechanisms/hypothetical models of Z-DNA transition and its implications in AD. We propose that Z-DNA is formed in the promoter region of the APP, and Presenilin genes and Z-DNA may absorb the negative supercoils at that region. This decreases the supercoil density, altering the domain's native supercoiling state and facilitates the binding of effectors, which positively regulate gene expression of AD-related genes like APP and Presenilin. Further, it is presumed that Z-DNA may be involved in the down regulation of genes involved in Abeta clearance, anti-oxidant and defense mechanisms in AD. The proposed working model is novel and reveals possible triggering factors or precursors, which regulate the modulation of the supercoiling level of DNA involving putative Z-DNA forming sequences and regulatory proteins binding to DNA in AD.


Study for luminescence performance of three methyl xanthine derivatives.
In this paper, the low-temperature phosphorescence (LTP), the low-temperature fluorescence (LTF), the paper substrate room-temperature phosphorescence (PS-RTP) and the room fluorescence (RTF) properties of caffeine (CF), theophylline (TP), and theobromine (TB) are investigated and compared, and some rules are found out: their maximal excitation wavelength and emission wavelength are in the range of 270-300 nm and 395-445 nm, respectively. And the PS-RTP characters of lifetime, polarization and quanta yield are also investigated and compared. It is found that their lifetimes of PS-RTP are all in the level of 0.1s. They belong to long-life phosphorescence and their PS-RTP spectra are incompletely polarized.


Exploration on the gap of single- and double-loop learning of balanced scorecard and organizational performance in a health organization.
This paper addresses and interprets learning styles, namely, single- and double-loop learning, of BSC implementation in the background of healthcare organizaiton/industry, through which barriers and facilitators are inducted for the BSC for the healthcare industry. Samples of this study are from a community hospital with 290 beds was probed with samples of 34 BSC members interviewed. Based on the qualitative research's grounded theory, the transcript data of this study were analyzed using open, axial, and selective coding through NVIVO 10.0. By using single- and double-loop learning, this study distinguishes between adding and changing a health organization's specific capabilities, routines or abilities. Findings of this study indicated that BSC learning is more likely to improve the efficiency of the strategic management and strengthen the company's existing capabilities and routines; but it is not possible for single-loop learning to develop new capabilities. This study contributes to indicate that single-loop learning can be useful facilitators for organizational learning via affecting the positive performance of the organization, because employees are in favor of following existing routines and rules and allowing the employees to see the meaning of this balanced scorecard. However, employees still do not have the power to make changes they expect, because they do not have the power and right to change. The purpose of this research is to evaluate organizational learning performance via the implementation of the balanced scorecard in order to understand the mechanism's impact on organizational development. In short, this paper contributes practically to depict the process of executing BSC in learning organization in detail, and theoretically to understand the mechanism in optimizing organizational learning effect via BSC implementation through discussion of (1) downward penetration of single-loop learning from organization vision and goals, and upward following and promotion of double-loop learning of sub-units in the form of routines, norms, action plans and others; (2) ways of eliminating the gap by linking organizational member's values with the organization's vision in the form of giving individuals opportunities to make their own interpretation of learning results in the workplace.


Message in the bottle: regulation of the tumor microenvironment via exosome-driven proteolysis.
Exosomes comprise a subtype of extracellular vesicles involved in cell-to-cell communication, specifically by transporting biological molecules, such as proteins and nucleic acids, to either local or more distant recipient cells, thus triggering distinct biological behaviors. Included in the exosome cargo is frequently a wide range of proteolytic enzymes, such as the matrix metalloproteinases (MMPs), the disintegrin and metalloproteinases (ADAMs), and the ADAM with thrombospondin-like motifs (ADAMTSs), whose functions contribute to the development and progression of cancer. In recent years, extensive research on the potential use of exosomes in diagnostic and therapeutic applications for personalized medicine has emerged, but the targeting of the proteolytic cargo of exosomes has not been fully exploited in this direction. In this review, we aim to explore both the mechanistic and the translational importance of proteolytic enzymes carried by the tumor cell-derived exosomes, as well as their role in the acquisition and support of certain hallmarks of cancer.


Palmar Warming for Radial Artery Vasodilation to Facilitate Transradial Access: A Randomized Controlled Trial.
To investigate the efficacy of palmar warming to induce radial artery vasodilation. After informed consent was obtained, healthy volunteers (n = 45) were randomized 2:1 in palmar warming and control groups, respectively, for this prospective, randomized, single-blind clinical trial (NCT03620383). The palmar warming group was given a warm, commercially available, air-activated heat pack (Kobayashi Consumer Products LLC, Dalton, Georgia) to hold in the left hand for palmar warming. The control group was given a deactivated version of the same heat pack. Left radial artery cross-sectional area (CSA) measurements were obtained at baseline and in 5-minute intervals up to 20 minutes in both groups. Differences in the trends of changes in the radial artery CSA between palmar warming and control groups were examined with the age- and sex-adjusted repeated measure analysis of variance. Propensity score-matched treatment effect analysis was conducted to quantify the effect of heat on radial artery CSA. The palmar warming group and the control group were significantly different in terms of subject sex (males/females: 7/23 and 10/5, respectively; P = .005) and baseline CSA (2.5±0.2 mm2 vs 3.2±0.3 mm2, respectively; P = .014). Radial artery CSA showed an increasing trend over time in the palmar warming group compared to a stable trend over time in the control group (P < .0001). Propensity score-matched comparison showed a 43.9% increase (95% confidence interval: 34.1%-53.8%) in CSA in the palmar warming group compared to the control group (P < .0001). The palmar warming technique is effective at dilating the radial artery and may be a beneficial technique to facilitate transradial access.


Late-onset attention-deficit/hyperactivity disorder as a differential diagnosis of dementia: a case report.
Although adult attention-deficit/hyperactivity disorder has recently gained increased attention, few reports on attention-deficit/hyperactivity disorder in the pre-elderly or elderly have been published. Here, we present the case of a patient with attention-deficit/hyperactivity disorder who gradually developed dementia-like symptoms as she aged, which initially made her condition difficult to distinguish from early onset Alzheimer's disease. This report illustrates that some types of attention-deficit/hyperactivity disorder may be misdiagnosed as dementia. The patient was a 58-year-old woman. Although she presented with a tendency for inattentiveness and forgetfulness since childhood, she did not have a history of psychiatric disorders prior to consultation. Around the age of 52 years, her inattentiveness and forgetfulness gradually progressed, and at 57 years of age, she became inattentive and forgetful that it interfered with her work and daily life. For example, she forgot meetings with important clients and transferred money to the wrong bank account; these failures resulted in poor management of her company. At home, she experienced increasing difficulties with remembering prior commitments with her family and misplacing items, which her family members noticed. With the encouragement of her family and employees, who worried that she was suffering from dementia, she visited our memory clinic, whereby she was suspected of having early onset Alzheimer's disease. However, neuropsychological tests and brain imaging evaluations did not reveal any significant abnormalities. After dismissing various possible diagnoses, including dementia, other organic diseases, mood disorders, and delirium, we diagnosed her with attention-deficit/hyperactivity disorder. Treatment with 18 mg of methylphenidate was initiated, and significant improvements in her symptoms were observed within a few days; for example, she stopped losing her things, was able to concentrate for long durations, and could complete more tasks than she could before treatment. Since initiating treatment, she has returned to work and has been able to perform her daily activities without difficulty. This case supports that some patients with late-onset attention-deficit/hyperactivity disorder may gradually develop dementia-like symptoms during the pre-elderly and elderly stages of life. Therefore, clinicians should consider late-onset attention-deficit/hyperactivity disorder as a differential diagnosis of some types of dementias.


A relevant in vitro eukaryotic live-cell system for the evaluation of plasmodial protein localization.
Understanding the functional genomics and proteomics of plasmodia underpins the development of new approaches to antimalarial chemotherapy. Although genome databanks (e.g. PlasmoDB) and biocomputing tools (e.g. PlasMit, PlasmoAP, PATS) are useful in providing a global albeit predictive view of the myriad of about 5000 genes, only 40% are annotated, with few cases of endorsed subcellular localizations of the corresponding proteins in animal models. Progress in plasmodial protein trafficking has been hampered by the lack of a simple yet reliable method for studying subcellular localization of plasmodial proteins. In this study, we have used a combination of fluorescent markers, organelle-specific probes, phase contrast microscopy, and confocal microscopy to locate a selection of signal peptides from 10 plasmodial proteins in CHO-K1 cells. These eukaryotic cells serve as an in vitro living system for studying the cellular destinations of four mitochondrial-targeted TCA cycle proteins (citrate synthase, CS; isocitrate dehydrogenase, ICDH; branched chain alpha-keto-acid dehydrogenase E1alpha subunit, BCKDH; succinate dehydrogenase flavoprotein-subunit, SDH), two nuclear-targeted proteins (histone deacetylase, HDAC; RNA polymerase, RPOL), two apicoplast-targeted proteins (pyruvate kinase 2, PK2; glutamate dehydrogenase, GDH), and two cytoplasmic resident proteins (malate dehydrogenase, MDH; glycerol kinase, GK). The respective localizations of these malarial proteins have complied with the selected molecular targets, viz. mitochondrial, nuclear and cytoplasmic. Interestingly, MDH that is widely known to be resident in eukaryotic mitochondria was found to be cytoplasmic, probably due to the absence of molecular target sequences. Since the localization of plasmodial proteins is central to the authentication of their pathophysiological roles, this experimental system will serve as a useful a priori approach.


Determining the impact of individual ventral hernia repair complications on patient-reported quality of life.
Ventral hernia repair (VHR) postoperative complications vary in presentation, management, and severity. The aim of this study is to determine the impact of individual postoperative complications on long-term quality of life (QoL) after VHR. Data from the Abdominal Core Health Quality Collaborative were analyzed retrospectively. Propensity score matching compared 1-year postoperative Hernia-Related Quality of Life Survey (HerQLes) summary scores between non-wound events (NWE), surgical site infection (SSI), and surgical site occurrence requiring procedural intervention (SSOPI) versus No-Complications. 2796 patients who underwent VHR between 2013 and 2022 met the study criteria. Patients with SSI and SSOPI had lower QoL vs No-Complications (median (Interquartile range): 71 (40-92) vs 83 (52-94), P = 0.02; 68 (40-90) vs 78 (55-95), P = 0.008). NWE vs no-complications HerQLes score differences were similar (83 (53-92) vs 83 (60-93), P = 0.19). Wound events seem to have larger impact on patients' long-term QoL compared to NWE. Continued and aggressive efforts including preoperative optimization, technical points, and appropriate use of minimally invasive techniques can continue to reduce impactful wound events.


Determination of Prevalence and Risk Factors of Infection with Babesia ovis in Small Ruminants from West Azerbaijan Province, Iran by Polymerase Chain Reaction.
Small ruminants' babesiosis caused by Babesia ovis, is transmitted during blood feeding by infected ticks and is the most economically important tick-borne disease in tropical and subtropical areas. This study was carried out to to estimate the infection rate of B. ovis in sheep and goats by PCR. We have analysed risk factors that might influence infection of sheep and goats with B. ovis. A total 402 blood samples were examined microscopically for the presence of Babesia infection. All samples were tested by PCR. During sampling, whole body of each animal and farm dogs was examined for the presence of ticks. Forty-two animals (10.4%) were positive for Babesia spp. upon microscopic examination, whereas 67 animals (16.7%) yielded the specific DNA for B. ovis of which 52 animals were sheep and 15 animals were goats. Twenty-nine farms (72.5%) were found positive for B. ovis. The percentage of positive animals in each location varied from 13 % to 20 %. The relative risk of the presence of ticks in sheep and goats (P< 0.01) and farm dogs (P< 0.01) for PCR- positive results for B. ovis in sheep and goats was found 3.8 and 2.9, respectively. A total of 747 ticks identified as Rhipicephalus bursa, R. sanguineus and R. turanicus on the basis of morphological features. Other animal species besides dogs may also be risk factors for babesiosis in sheep and goats. Also, R. bursa may play an important role as a vector of the parasite in Iran.


Tissue microarray-based study of patients with lymph node-positive breast cancer shows tyrosine phosphorylation of signal transducer and activator of transcription 3 (tyrosine705-STAT3) is a marker of good prognosis.
Although lymph node-positive breast cancers are associated with poorer prognosis, individual patients may have different clinical outcomes. Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signalling pathways. The goal of this study was to determine the prognostic value of phosphorylated (tyrosine705)-STAT3 in node-positive breast cancer patients. Immunohistochemical analysis of Phospho- STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of Phospho-STAT3 was correlated with survival outcome, and clinical and pathological parameters. Out of 125 interpretable tumours, positive Phospho- STAT3 nuclear expression was seen in 35 (28%) of tumours. There was no significant relationship between Phospho-STAT3 expression and clinical-pathological parameters including age, hormonal receptor status, grade and tumour size. Interestingly positive tumours had a significantly improved disease-free survival at 5 years (p=0.035). Additionally, positive Phospho-STAT3 nuclear expression was correlated with significantly improved survival at both 5 years (p=0.023) and 10 years (p=0.026). Finally, in multivariate analyses Phospho-STAT3 was found to be an independent prognostic marker of overall survival in node-positive breast cancer patients. These findings support the role of Phospho- STAT3 as an important independent prognostic marker in node-positive breast cancer patients.


Stroke Mimics: A five-year follow-up study from the Qatar Stroke Database.
Mimics comprise a third of patients presenting with an acute stroke. There is limited information on their natural history. We evaluate long term major cardiovascular events (MACE) in stroke mimics in a prospective database from Qatar. Between Feb 2014 and Jan 2019, 481 patients (male: 238; female: 243) mean age 57.5 years (±18.0), with 399 (83%) medical mimics and 82 (17%) functional mimics were evaluated. Imaging revealed previous old stroke in 26.6% and small vessel disease in 5%. MACE occurred in 57 (11.9%) and there were 31 deaths (6.4%) with majority of deaths (5.6%) from cardiovascular causes. MACE was significantly higher in patients with previous stroke, p < 0.0001), coronary artery disease, p = 0.002), diabetic, p = 0.01), and hypertensive on admission, p < 0.0001. MACE were also significantly higher in patients where imaging showed a previous stroke, p = 0.006). The occurrence of MACE during follow-up suggests that patients with existing vascular disease require aggressive management of vascular risk factors.


Carpal tunnel syndrome in pregnancy. A prospective study.
In this prospective study, 56 women (2.3%) of 2,358 (47% nulliparous and 53% multiparous) delivered during a 12-month period at the Department of Obstetrics and Gynecology, Malmö General Hospital, had symptoms of carpal tunnel syndrome during pregnancy. All (33 nulliparous and 23 multiparous women) were examined, at the outpatient's maternity care unit and within 4-5 weeks from the time of debut of symptoms, by a specialist in hand surgery. At that time the most common symptoms were paresthesia and nocturnal pain. Twenty-nine had signs of reduced sensibility and 14 of them had a positive two-point discrimination test. All had generalized edema. Conservative treatment with splinting of the wrist at night made 46 out of 56 symptom-free. Of the remaining 10 women, 3 had to be operated on, whereas 7 received only conservative treatment, as the expected time for parturition was very close. One of them had to be operated on after delivery. In conclusion, carpal tunnel syndrome during pregnancy is most common in primiparas with generalized edema. Conservative treatment is sufficient for symptom relief in most women (80%) but a few cases need operative intervention to abolish the severe pain and to avoid disturbances of hand function.


Oxal hydroxamic acid derivatives with inhibitory activity against matrix metalloproteinases.
Several amines, amino acid derivatives and low molecular weight peptides containing an amide-bound oxal hydroxamic acid moiety have been synthesized and tested for their inhibitory effects towards native human gelatinase B (MMP-9) and the catalytic domains of the membrane type MT1-MMP (MMP-14) and of neutrophil collagenase (MMP-8). A number of these compounds exhibited considerable inhibitory activity against the tested metalloproteinases.


Treatment of Multi-drug Resistant Tuberculosis Causing Tubulopathy - Gitelman-like Syndrome.
Treatment of multi-drug resistant (MDR) tuberculosis (TB) includes aminoglycosides and ethionamide. A 16-year-old girl presented with sudden onset of paralysis, dyselectrolytemia mimicking Gitelman syndrome, and ethionamide-induced hypothyroidism. Monitoring electrolytes during MDR-TB treatment is recommended to prevent life-threatening complications.


Cardiac markers and their point-of-care testing for diagnosis of acute myocardial infarction.
Acute myocardial infarction (AMI) is the world's leading cause of mortality and morbidity. Therefore, quick and reliable diagnostics of AMI is extremely critical. Compared to the traditionally used central laboratory tests (CLT), which can be time-consuming and expensive, point-of-care testing (POCT) for AMI-indicative cardiac markers provides a convenient means for rapid diagnostic assays to be performed at the site of patient care delivery. In this article, the etiology and diagnosis of AMI are introduced, and some typical cardiac markers and their clinical applications are reviewed. Furthermore, the various POC cardiac marker devices that are currently available, the benefits of using cardiac marker POC assays, and challenges that cardiac marker POCT are facing are also discussed.


Clinical update on fluid therapy and nutritional support in acute pancreatitis.
The aim of this focused review is to provide a valuable and updated source of information for clinical practice on fluid therapy (FT) and nutritional support in acute pancreatitis (AP). The review encompasses important new clinical information that has become available for understanding and offering these specific treatments since the 2013 publication of two guidelines, both the joint International Association of Pancreatology and American Pancreatic Association and the American College of Gastroenterology. The 2015 Revised Japanese Guideline is discussed selectively. To this end, the review is divided into 7 sections, including timing and cause of mortality; severity classification systems; predicting severity; response to treatment; nutritional support; fluid therapy and steps for further research. In mild AP, begin oral feeding when nausea, vomiting and abdominal pain are improving. In (predicted) severe AP, feeding decisions should commence by 72 h, offering oral feeding if GI symptoms improve or enteral feeding if patients are symptomatic and/or intolerant to orals. All patients should be offered goal-directed FT during the first 6-12 h of presentation. Cautious FT is advised in those age >55 years or with preexisting organ failure or predictors of developing fluid sequestration.


Hemodynamic markers of pulmonary vasculopathy for prediction of early right heart failure and mortality after heart transplantation.
Elevated pulmonary vascular resistance (PVR) is broadly accepted as an imminent risk factor for mortality after heart transplantation (HTx). However, no current HTx recipient risk score includes PVR or other hemodynamic parameters. This study examined the utility of various hemodynamic parameters for risk stratification in a contemporary HTx population. Patients from seven German HTx centers undergoing HTx between 2011 and 2015 were included retrospectively. Established risk factors and complete hemodynamic datasets before HTx were analyzed. Outcome measures were overall all-cause mortality, 12-month mortality, and right heart failure (RHF) after HTx. The final analysis included 333 patients (28% female) with a median age of 54 (IQR 46-60) years. The median mean pulmonary artery pressure was 30 (IQR 23-38) mm Hg, transpulmonary gradient 8 (IQR 5-10) mm Hg, and PVR 2.1 (IQR 1.5-2.9) Wood units. Overall mortality was 35.7%, 12-month mortality was 23.7%, and the incidence of early RHF was 22.8%, which was significantly associated with overall mortality (log-rank HR 4.11, 95% CI 2.47-6.84; log-rank p < .0001). Pulmonary arterial elastance (Ea) was associated with overall mortality (HR 1.74, 95% CI 1.25-2.30; p < .001) independent of other non-hemodynamic risk factors. Ea values below a calculated cutoff represented a significantly reduced mortality risk (HR 0.38, 95% CI 0.19-0.76; p < .0001). PVR with the established cutoff of 3.0 WU was not significant. Ea was also significantly associated with 12-month mortality and RHF. Ea showed a strong impact on post-transplant mortality and RHF and should become part of the routine hemodynamic evaluation in HTx candidates.


Pain assessment following burn injury in Australia and New Zealand: Variation in practice and its association on in-hospital outcomes.
Pain is common following burn injury. Pain assessments are required to ensure appropriate pain management is provided. This study aimed to describe the prevalence and potential variation in practice of validated and documented pain assessment following burn injury in Australian and New Zealand burn units, identify clinical characteristics of patients who receive a pain assessment, and explore the associations between receiving a pain assessment and in-hospital outcomes. Burns Registry of Australia and New Zealand (BRANZ) admissions data were extracted. Responses to the pain assessment field were presented by contributing burns unit using frequencies and percentages. Demographic, injury severity and event, and in-hospital outcomes data were assessed. There were 3009 admissions over the study period; 2481 of these received an assessment. The rate of pain assessment varied considerably between units. Women and adult patients more commonly received a pain assessment. Receiving a pain assessment was associated with a 53% adjusted increase in LOS. There are differences in the profile of patients who receive a pain assessment after burn injury. The findings of this study will be reported back to designated burns units to improve pain assessment rates and patient care.


Time-lapse, photoactivation, and photobleaching imaging of nucleolar assembly after mitosis.
Nucleolus assembly starts in telophase with the benefit of building blocks passing through mitosis and lasts until cytokinesis generating the two independent interphasic cells. Several approaches make it possible to follow the dynamics of fluorescent molecules in live cells. Here, three complementary approaches are described to measure the dynamics of proteins during nucleolar assembly after mitosis: (1) rapid two-color 4-D imaging time-lapse microscopy that demonstrates the relative localization and movement of two proteins, (2) photoactivation that reveals the directionality of migration from the activated area, and (3) fluorescence recovery after photobleaching (FRAP) that measures the renewing of proteins in the bleached area. We demonstrate that the order of recruitment of the processing machineries into nucleoli results from differential sorting of intermediate structures assembled during telophase, the prenucleolar bodies.


Organic gelatin-coated ZnNPs for the production of biodegradable biopolymer films.
Petroleum-based polymers have raised significant environmental concerns. It is critical to create compostable, good biocompatibility, and nontoxic polymers to replace petroleum-based polymers. Thus, this research was performed to extract the gelatin from fish waste cartilage and coated it over the surface of spherical shaped pre-synthesized ZnNPs along with a suitable plasticizer to produce the biodegradable film. The presence of gelatin on the surface of ZnNPs was first confirmed using UV-visible spectrophotometers, as well as the characteristic functional groups involved in the coating were investigated using Fourier-Transform Infrared Spectroscopy (FTIR). The morphological appearance of gelatin coated ZnNPs was ranged from 41.43 to 52.31 nm, the shape was found as platonic to pentagonal shape, and the fabricated film was observed through Scanning Electron Microscope (SEM). The thickness, density, and tensile strength of fabricated film were found to be 0.04-0.10 mm, 0.10-0.27 g/cm3, and 31.7 kPa. These results imply that the fish waste cartilage gelatin coated ZnNPs-based nanocomposite can be used for film preparation as well as a wrapper for food and pharmaceutical packaging.