The clinical significance of the incorporation of tissue Doppler imaging into low-dose Dobutamine stress echocardiography in patients with aortic stenosis prior to Transcatheter aortic valve implantation.
Low-dose dobutamine stress echocardiography (DSE) is indicated in patients with low flow (stroke volume index [SVi] < 35 ml/m2) low gradient (mean pressure gradient < 40 mmHg) and left ventricular ejection fraction (LVEF) < 50% aortic stenosis (AS) to assess LV contractile reserve (> 20% increase in SVi) and severity grade of AS. Severe AS is defined by a mean pressure gradient of 40 mmHg occurring at any time during the test when aortic valve area remains < 1.0 cm2. This case report highlights the utility of mitral annular systolic velocity (S') by tissue Doppler imaging and peak LV outflow tract (LVOT) velocity as markers of LV intrinsic contractile function during DSE in a patient with low flow low gradient AS and reduced EF prior to transcatheter aortic valve implantation (TAVI). Mitral annular S' and peak LVOT velocities are reliable markers of LV intrinsic contractile function and should be incorporated into routine low-dose DSE.


UPDATED PROTOCOL: Universal school-based programmes for improving social and emotional outcomes in children aged 3-11 years: An evidence and gap map.
This is the protocol for an evidence and gap map. The objective of this EGM is to identify and map all primary studies (including randomised and cluster randomised trials) and systematic reviews on universal, school-based social and emotional learning programmes for young children (3-11 years) to create a live, searchable, and publicly available evidence and gap map.


Association between i.v. thrombolysis volume and door-to-needle times in acute ischemic stroke.
Centralization of intravenous thrombolysis (IVT) for acute ischemic stroke in high-volume centers is believed to improve the door-to-needle times (DNT), but limited data support this assumption. We examined the association between DNT and IVT volume in a large Dutch province. We identified consecutive patients treated with IVT between January 2009 and 2013. Based on annualized IVT volume, hospitals were categorized as low-volume (≤ 24), medium-volume (25-49) or high-volume (≥ 50). In logistic regression analysis, low-volume hospitals were used as reference category. Of 17,332 stroke patients from 11 participating hospitals, 1962 received IVT (11.3 %). We excluded 140 patients because of unknown DNT (n = 86) or in-hospital stroke (n = 54). There were two low-volume (total 101 patients), five medium-volume (747 patients) and four high-volume hospitals (974 patients). Median DNT was shorter in high-volume hospitals (30 min) than in medium-volume (42 min, p < 0.001) and low-volume hospitals (38 min, p < 0.001). Patients admitted to high-volume hospitals had a higher chance of DNT < 30 min (adjusted OR 3.13, 95 % CI 1.70-5.75), lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.39, 95 % CI 0.16-0.92), and a lower mortality risk (adjusted OR 0.45, 95 % CI 0.21-1.01), compared to low-volume centers. There was no difference in DNT between low- and medium-volume hospitals. Onset-to-needle times (ONT) did not differ between the groups. Hospitals in this Dutch province generally achieved short DNTs. Despite this overall good performance, higher IVT volumes were associated with shorter DNTs and lower complication risks. The ONT was not associated with IVT volume.


Indispensable role of melatonin, a scavenger of reactive oxygen species (ROS), in the protective effect of Akkermansia muciniphila in cadmium-induced intestinal mucosal damage.
The gastrointestinal tract is the main target of cadmium toxicity. However, whether Akkermansia muciniphila (A. muciniphila), which has been reported to be the next generation of promising probiotics, can alleviate cadmium-induced intestinal damage has not been investigated. In this study, we found that compared to the cadmium exposure group, mice gavaged with A. muciniphila showed less severe intestinal mucosal damage, with improved bodyweight, colon length, a decline in inflammation, and significantly increased glutathione and goblet cell numbers. Meanwhile, melatonin was interestingly found to be strikingly increased after A. muciniphila treatment. We then demonstrated that melatonin also could ameliorate the intestinal mucosal damage caused by cadmium through scavenging reactive oxygen species (ROS) and increasing the number of goblet cells. Furthermore, mice treated with inhibitors had a low level of melatonin and could not reproduce the beneficial effects of the A. muciniphila. Our results implied that the regulation of melatonin production by A. muciniphila is associated with an increase in enterochromaffin cells number, which determine melatonin secretion. This study indicated that the A. muciniphila-melatonin axis reduces cadmium-induced damage by increasing the goblet cells and scavenging the ROS, which may guide the prevention of the toxic effects of heavy metals.


Characterization of three ascovirus isolates from cotton insects.
Three new ascovirus isolates were discovered from lepidopteran larvae in cotton fields in Blackville, South Carolina, USA, and were named TnAV-2c, TnAV-2d, and HvAV-3f. TnAV-2c and TnAV-2d were compared by restriction endonuclease (REN) profiles and found to be similar. HvAV-3f was isolated from Helicoverpa zea, and bears remarkable dissimilarity in REN profiles to the reported SeAV-5a from Spodoptera exigua but DNA hybridization shows they are closely related. Major capsid protein (MCP) and delta DNA polymerase from the three isolates were sequenced, which suggests the three isolates are novel. Phylogenetic analyses showed that TnAV-2c is distantly related to other lepidopteran ascoviruses. HvAV-3f and SeAV-5a may also be variants of the same species based on Southern, Western, and MCP/DNA polymerase gene sequence analyses. High levels of TnAV-2 infection in an H. zea population (as high as 74%) were recorded in a cotton field in Blackville, SC. Observations in this field showed that infection by ascovirus altered the feeding behavior of H. zea larvae.


Coping style and depressive symptomatology during pregnancy in a private setting sample.
To evaluate the association of antenatal depressive symptomatology (AD) with life events and coping styles, the hypothesis was that certain coping strategies are associated to depressive symptomatology. We performed a cross sectional study of 312 women attending a private clinic in the city of Osasco, São Paulo from 27/05/1998 to 13/05/2002. The following instruments were used: Beck Depression Inventory (BDI), Holmes and Rahe Schedule of Recent Events (SSRS), Folkman and Lazarus Ways of Coping Questionnaire and questionnaire with social-demographic and obstetric data. women with no past history of depression, psychiatric treatment, alcohol or drug abuse and no clinical-obstetrical complications. Odds ratios and 95% CI were used to examine the association between AD (according to BDI) and exposures variables. Hypothesis testing was done with Chi2 tests and ap value < .05. AD occurred in 21.1% of pregnant women. By the univariate analyses, education, number of pregnancies, previous abortion, husband income, situation of marriage and score of SSRS were associated with AD. All coping styles were associated with AD, except seeking support and positive reappraisal. By the multivariate analyses, four coping styles were kept in the final model: confront (p = .039), accepting responsibility (p < .001), escape-avoidance (p = .002), problem-solving (p = .005). AD was highly prevalent and was associated with maladaptive coping styles.


Effect of water deprivation on the centrally-mediated hypertensive response to clonidine in freely moving, normotensive rats.
Effects of water deprivation on pressor responses to centrally and peripherally administered clonidine was investigated in freely moving, normotensive rats with chronic guide cannula and catheters implanted into the abdominal aorta via the femoral artery. In normal hydrated rats, intracerebroventricularly (i.c.v.) injected clonidine (10 and 20 micrograms) produced a dose-dependent and long-lasting rise in mean blood pressure (MBP) concomitant with a decrease in heart rate. However, a significant depressor response was not observed for up to 90 min. In 48 hr dehydrated rats, the pressor response to i.c.v. injected clonidine (10 and 20 micrograms) was significantly depressed and a depressor response appeared. Intravenously (i.v.) administered clonidine (25 micrograms/kg) in normal hydrated rats also produced a long-lasting pressor response following an initial rapid rise in MBP. The long-lasting pressor response to i.v. injected clonidine was abolished after water deprivation for 48 hr, whereas the initial rise in MBP was less affected. These results suggest that clonidine elicits centrally-mediated pressor response, which is influenced by body fluid volumes.


Cytoskeleton alterations in non-alcoholic fatty liver disease.
Due to its extremely high prevalence and severity, non-alcoholic fatty liver disease (NALFD) is a serious health and economic concern worldwide. Developing effective methods of diagnosis and therapy demands a deeper understanding of its molecular basis. One of the strategies in such an endeavor is the analysis of alterations in the morphology of liver cells. Such alterations, widely reported in NAFLD patients and disease models, are related to the cytoskeleton. Therefore, the fate of the cytoskeleton components is useful to uncover the molecular basis of NAFLD, to further design innovative approaches for its diagnosis and therapy. Several cytoskeleton proteins are up-regulated in liver cells of NAFLD patients. Under pathological conditions, keratin 18 is released from hepatocytes and its detection in the blood emerges as a non-invasive diagnosis tool. α-Smooth muscle actin is up-regulated in hepatic stellate cells and its down-regulation has been widely tested as a potential NALFD therapeutic approach. Other cytoskeleton proteins, such as vimentin, are also up-regulated. NAFLD progression involves alterations in expression levels of proteins that build the liver cytoskeleton or associate with it. These findings provide a timely opportunity of developing novel approaches for NAFLD diagnosis and therapy.


Optimal control of root nodulation - Prediction of life history theory of a mutualistic system.
Legumes produce root nodules containing symbiotic rhizobial bacteria that convert atmospheric molecular nitrogen into ammonia or related nitrogenous compounds. The host plant supplies photosynthetic products to root nodules forming a mutualistic system. Legumes have physiological mechanisms for regulating nodule production with chemical signals produced in leaves, called the autoregulation of nodulation. In this paper, we discuss the optimal number of root nodules that maximizes the performance of the host plant. Here, we study two models. In the stationary plant model, the acquired photosynthetic products minus cost and loss are used for reproduction. In the growing plant model, the excess material is invested to produce leaves, roots, and root nodules, resulting in the exponential growth of the whole plant. The analysis shows that having root nodules is beneficial to the plant for a high leaf nitrogen content, faster plant growth rate, a short leaf longevity, a low root/shoot ratio, and low soil nutrient concentration. We discuss the long-distance control of nodulation-autoregulation and dependence on the environmental conditions of terrestrial plants considering these results.


A new genus and species of Cicadellini (Hemiptera: Cicadellidae) from China.
The leafhopper genus Atkinsoniella was originally established by Distant (1908) for two species with A. decisa as type species. So far, 75 valid species are known worldwide and of these, 63 are from China (Yang et al. 2011). Because Atkinsoniella is a very large and morphologically heterogeneous genus it is desirable to recognize smaller groups of species with distinctive characteristics.


Axillary padding as an alternative to closed suction drain for ambulatory axillary lymphadenectomy: a prospective cohort of 207 patients with early breast cancer.
Axillary lymphadenectomy performed without the use of a drain but with padding of the axilla is feasible and safe on an outpatient basis in the setting of conservative surgery for breast cancer. Prospective clinical study. Public oncology center. Two hundred seven patients were treated in our oncology center between January 11 and December 28, 1999, by means of this method of axillary lymphadenectomy based on axillary padding without a drain. One-day surgery was offered to each patient. At the end of each functional axillary lymphadenectomy, the axilla was padded with the use of axillary aponeurosis and local muscles. Axillary suction drains were not used at all in this series of patients. Prospective assessment was performed, without randomization, with regard to the length of hospital stay, the reasons for postoperative conversion from 1-day surgery to traditional hospitalization, and postoperative complications. Eighty-seven (42.0%) of the 207 patients underwent a 1-day procedure. In the 1-day surgery group, 87 (84.5%) of the 103 patients benefited from a true 1-day surgery procedure. The main reasons for conversion were nausea and anxiety rather than surgical complications. Hospital stay never exceeded 3 days. The most common postoperative complication was axillary seroma, with an average incidence of 22.2%. Breast-preserving surgery with axillary lymphadenectomy and padding of the axilla, precluding the use of a drain, is feasible and safe on a 1-day surgery basis for selected consenting patients.


iTRAQ and PRM-Based Proteomic Analysis Provides New Insights into Mechanisms of Response to Triple Therapy in Patients with Rheumatoid Arthritis.
Approximately 30% of patients with rheumatoid arthritis (RA) respond poorly to combination therapy of multiple drugs. The molecular mechanisms of different responses to methotrexate + leflunomide + infliximab therapy in patients with RA were explored in this study. Infliximab was administered to patients with RA whose disease activity score was higher than 5.1 after 1 month of combination therapy with methotrexate and leflunomide. After 14 weeks of undergoing triple therapy, patients with RA were classified as responders and non-responders. Protein profiles at baseline and 14th week were investigated via isobaric tags for relative and absolute quantification (iTRAQ), and proteins with significant differences ≥1.2 folds change or ≤0.8 folds change were defined as differentially expressed proteins (DEPs). Overlapping DEPs between responders and non-responders were confirmed by parallel reaction monitoring (PRM). Bioinformatic analyses were performed for DEPs. The results revealed 5 non-responders (NRs) and 15 responders (Rs). iTRAQ analysis indicated 13 overlapping DEPs and included 6 opposite change DEPs such as testicular tissue protein Li 70, cofilin 1, fibrinogen beta chain, galectin-10, serotransferrin (TF) and albumin. The difference in serotransferrin between responders and non-responders confirmed by PRM was significant. Verification by PRM indicated that TF was elevated in the Rs group and was reduced in the NRs group. Bioinformatic analysis indicated that serotransferrin was involved in the hypoxia-inducible factor-1 pathway and ferroptosis. Serotransferrin-related molecular mechanism may be a new direction to study refractory RA.


Towards an estimate of chloride permeability in the smooth muscle of guinea-pig vas deferens.
Cl movements across the cell membranes of smooth muscle from the guinea-pig vas deferens were measured using Cl-sensitive micro-electrodes and 36Cl fluxes. The rate constants for the loss of Cl ions measured by both methods under a variety of conditions were used to calculate the apparent Cl permeability (PCl). If it is assumed that the initial rate of decline of the intracellular Cl activity (aiCl) on removal of extracellular Cl (Clo) represents net transmembrane Cl movement, the apparent PCl was 3-6 X 10(-8) cm s-1. This value is in good agreement with those calculated from the rate constant of 36Cl efflux into both normal Krebs solution (steady-state) and Cl-free solution. Such a value for PCl predicts a large depolarization on removal of Clo, but only a minimal change was recorded. It also predicts that changes in membrane potential (Em) would affect aiCl; furthermore that removal of Clo would increase membrane resistance and thus the hyperpolarization observed on reactivation of the electrogenic Na pump. Neither of these was observed. The PCl/PK ratio obtained from changes in Em on rapid changes in Clo and Ko gives a value for PCl which is an order of magnitude lower: 4 X 10(-9) cm s-1, using Casteels' (1969 b) value for PK. These observations can be reconciled by a substantial proportion of the measured Cl movements being carrier-mediated. The presence of the stilbene derivative DIDS greatly slowed both the steady-state efflux and uptake of 36Cl, as has previously been shown for the loss and reaccumulation of Cl ions on removal and replacement of Clo. PCl calculated in the presence of DIDS was about 5 X 10(-9) cm s-1. The nominal absence of CO2 and HCO3, which slows the reaccumulation and loss of Cl, had no effect on the steady-state fluxes. This indicates that the carrier operates in the self-exchange mode in the steady state.


Gene expression profile of epithelial-mesenchymal transition mediators in papillary thyroid cancer.
Platelet derived growth receptor alpha (PDGFRA) promotes the epithelial-mesenchymal transition (EMT) in thyroid follicular cells and is linked to lymphatic metastases in papillary thyroid cancer (PTC). We probed the regulatory network of genes linked to PDGFRA and EMT, comparing matched patient primary tumor and metastatic specimens, as well as engineered cell lines and ex vivo primary cultures with and without PDGFRA. Freshly isolated thyroid tumors with or without metastases, with matching neighboring benign or normal tissue, was isolated for comparative transcriptional analysis using a TaqMan Low Density array (TLDA) assay with genes representing important markers of EMT, cellular adhesion, apoptosis, differentiation, senescence, and signal transduction pathways in thyroid cancer. Transfected primary cultures and immortalized cell lines were also analyzed with respect to PDGFRA expression and cell phenotype. We reveal the consistent upregulation of serine protease DPP4 and structural protein SPP1 with the progression of PTC to metastatic disease, as well as with PDGFRA expression. Conversely, epithelial integrity gene TFF3 and transcription factor SOX10 were strongly down-regulated. This gene network also includes important mediators of EMT including DSG1, MMP3, MMP9, and BECN. We observed similar genomic changes in ex vivo normal thyroid cells transfected with PDGFRA that also exhibited a partially dedifferentiated phenotype. In particular, we observed lamellopodia with induction of PDGFRA and illustrate that DPP4 and SPP1 were upregulated in this process, with decreased TFF3 and SOX10 as seen in tissue specimens. PDGFRA did decrease nuclear protein levels of differentiation factor TTF1, but not the transcription of TTF1 and PAX8. We demonstrate that PDGFRA activates EMT pathways and decreases expression of genes favoring epithelial integrity, pushing follicular cells toward a dedifferentiated phenotype. SPP1 and DPP4, previously linked with adverse outcomes in thyroid cancer, appear to be regulated by PDGFRA. PDGFRA expression promotes metastatic disease through multiple EMT levers that favor formation of an invasive phenotype and increased metalloproteinase expression.


Trends in firearm production and firearm deaths in U.S. youth.
Firearms are now the leading cause of death for U.S. children and teens ages 0-19. The U.S. Department of Justice Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) reported data in 2022 on firearm production, for specific firearm types and calibers. We hypothesized there would be a correlation between firearm production and firearm deaths and nonfatal injuries in youth. All firearm deaths and nonfatal injury rates for youth ages 0-19 were extracted from the Centers for Disease Control and Prevention from 2001 to 2020. Firearm production from 2001 to 2020 was extracted from the 2022 ATF Firearms in Commerce Report for overall firearm production, production by weapon type and pistol caliber. Relationships between firearm death and injury and firearm production were evaluated using correlational analyses. Firearm death and nonfatal injury rates for youth increased from 2001 to 2020 by 48.2% and 69.2%, respectively, and firearm production increased 265% overall and 1298% for 9 mm pistols. There was no correlation between total firearm manufacturing and total firearm deaths or nonfatal injury rates from 2001 to 2020 (all r < 0.28). Pistol caliber (25 and 9 mm) was associated with total firearm deaths and nonfatal injuries (all r > 0.55). While total firearm manufacturing was not related to firearm deaths and injuries, except suicides, there were strong relationships between 9 mm pistol production and firearm deaths and injuries in youth. Firearm injuries are preventable; we must invest in stronger information systems that track details of firearms linked with deaths and injuries.


Primary spinal melanoma with bilateral papilledema.
A case of primary leptomeningeal malignant melanoma localized in the cervical region in a 41-year-old woman is presented. The only clinical finding was intracranial hypertension with papilledema. A diagnosis of primary CNS melanoma was made after dermatological and ophthalmological consultations, ruled out a metastatic lesion. Primary leptomeningeal melanoma is an extremely rare spinal tumor. Its clinical presentation with signs of increased intracranial pressure but without cord symptoms is unusual. Clinical features of this case including the radiological and histologic findings are described. Diagnosis as well as management are discussed.


Pleural recurrence and long-term survival after thoracotomy and thoracoscopic lobectomy.
There are concerns over procedure-related pleural dissemination during video-assisted thoracic surgery (VATS) lobectomy. We compared the incidence of pleural recurrence and long-term survival between patients undergoing thoracotomy and VATS lobectomy for non-small cell lung cancer (NSCLC) with visceral pleural invasion. From 2004 to 2009, 2,774 patients underwent curative-intent pulmonary resection for NSCLC at our institution. Of those, 478 patients were pathologically confirmed to have visceral pleural invasion by primary tumor. Among these, 239 patients (50%) underwent VATS lobectomy and 239 (50%) underwent thoracotomy lobectomy. Their medical records were retrospectively reviewed and a propensity score-matched analysis was performed. Matching based on propensity scores produced 167 patients in each group. There were no significant differences between two groups in age, sex, histologic type, tumor size, and pathologic N stage. The median follow-up duration was 52 months. During follow-up, 14 patients (8.4%) from the VATS group and 12 (7.2%) from the thoracotomy group had ipsilateral pleural recurrence (p = 0.735). There was no significant difference in the recurrence pattern between the two groups. Overall survival at 5 years was 83% and 74% in the VATS and thoracotomy groups, respectively (p = 0.16). Disease-free survival at 5 years was 65% and 62% in the VATS and thoracotomy groups, respectively (p = 0.45). Compared with thoracotomy, VATS lobectomy does not seem to increase the risk of procedure-related pleural dissemination in patients with NSCLC with visceral pleural invasion. Long-term survival and pattern of recurrence were similar between the two groups.


Ecotoxicological evaluation of selected pharmaceuticals to Vibrio fischeri and Daphnia magna before and after photooxidation process.
The aim of the research was the determination of the toxicity of photocatalytically treated water contaminated by different pharmaceuticals: chloramphenicol (CPL), diclofenac (DCF) or metoprolol (MT). Daphtoxkit F™ with Dapnia magna and Microtox(®) with Vibrio fischeri were used to evaluate the toxicity of the water before and after treatment. D. magna showed higher sensitivity to the presence of pharmaceuticals than V. fischeri. Generally, both tested organisms revealed the greatest sensitivity to the presence of CPL. The application of photocatalytic oxidation has resulted in decreased toxicity. It may confirm the reduction of high toxic parent compounds to less toxic metabolites. The toxicity was reduced in the range from 30% to 100% depending on pharmaceutical tested. The highest reduction of toxicity to V. fischeri and D. magna was observed to MT and CPL respectively. Depending on bioassay the toxicity decrease as follows: CPL>DCF>MT for D. magna and CPL>MT>DCF for V. fischeri.


Controlling the Secondary Surface Morphology of Electrospun PVDF Nanofibers by Regulating the Solvent and Relative Humidity.
This work presents a simple and reliable method for directly generating polyvinylidene fluoride (PVDF) nanofibers with secondary surface morphology (e.g., porous surfaces, rough surfaces, grooved surfaces, and interior porosity) by using single/binary solvent systems and relative humidity. We clarified the mechanisms responsible for the formation of these morphologies by systematically exploring the molecular interactions among the polymer, solvent(s), and water vapor. Our results proved that the formation of secondary surface morphology needed the presence of water vapor, a non-solvent of the polymer, at an appropriate level of relative humidity. The formation of secondary surface morphology was dependent on the speed of evaporation of the solvent(s) (ACE, DMF, and their mixtures), as well as the inter-diffusion and penetration of the non-solvent (water) and solvent(s). The results of N2 physical adsorption-desorption isotherms showed that the macro-porous fibers (> 300 nm) exhibited the highest specific surface area of 23.31 ± 4.30 m2/g and pore volume of 0.0695 ± 0.007 cm3/g, enabling the high oil absorption capacities of 50.58 ± 5.47 g/g, 37.74 ± 4.33 g/g, and 23.96 ± 2.68 g/g for silicone oil, motor oil, and olive oil, respectively. We believe this work may serve as guidelines for the formation of different structures of macro-porous, rough, and grooved nanofibers with interior porosity through electrospinning.


Towards robust and repeatable methods for studying interactions between jellyfish and microplastics.
Studies of microplastics are increasing exponentially and standard protocols are only beginning to be established. Jellyfish are considered susceptible to ingesting microplastics because they feed on small, suspended particles. Inconsistent approaches used to study interactions between jellyfish and microplastics, however, make comparisons among studies difficult. Here we review aspects of the methods used to sample jellyfish in the field and experimental approaches used in the laboratory to study interactions between jellyfish and microplastics, recommend some standard protocols and identify areas for further research. We highlight the need for experiments to be environmentally relevant, to study a greater diversity of species and to study different life history stages.


Is biofeedback-assisted pelvic floor muscle training superior to pelvic floor muscle training alone in the treatment of dysfunctional voiding in women? A prospective randomized study.
To compare the effectiveness of biofeedback-assisted pelvic floor muscle training (PFMT) and PFMT alone on voiding parameters in women with dysfunctional voiding (DV). The patients in group 1 (34 patients) were treated with biofeedback-assisted PFMT, and the patients in group 2 (34 patients) were treated with PFMT alone for 12 weeks. The 24-hour frequency, average voided volume, maximum urine flow rate (Qmax), average urine flow rate (Qave), post-void residual urine volume (PVR), and the validated Turkish Urogenital Distress Inventory (UDI-6) symptom scores were recorded before and after 12 weeks of treatment. At the end of treatment sessions, the Qmax and Qave values of the patients in group 1 were significantly higher than those in group 2, and the PVR in the patients in group 1 was significantly lower than those in group 2 (p=.026, .043, and .023, respectively). The average UDI-6 symptom scores of the patients in group 1 were significantly lower than those in group 2 (p=.034). Electromyography activity during voiding, in group 1 was significantly lower than in group 2 (41.2 vs. 64.7, respectively, p=.009). Biofeedback-assisted PFMT is more effective than PFMT alone in improving clinical symptoms, uroflowmetry parameters, and EMG activity during voiding.


Electron microscopic observation of the liver in portal hypertension following chronic exposure to vinyl chloride monomer.
Two patients with portal hypertension following chronic exposure to vinyl chloride monomer were studied histologically and ultrastructurally. Both cases showed non-cirrhotic portal hypertension accompanied by esophageal varices and splenomegaly. They proved hepatic fibrosis with conventional microscope. Ultrastructurally, there were large amounts of small myelin-like lamellar materials with electron density and remarkable proliferation and vesiculation of smooth endoplasmic reticulum in the cytoplasms of hepatocytes. The widened Disse's spaces, were the sinusoidal lining cells were arranged in multilayers, were plugged by collagenous fiber bundles. The finding may be consistent with the development of portal hypertension.


Depth-dependent drivers of soil microbial necromass carbon across Tibetan alpine grasslands.
Microbial necromass carbon (C) has been considered an important contributor to persistent soil C pool. However, there still lacks large-scale systematic observations on microbial necromass C in different soil layers, particularly for alpine ecosystems. Besides, it is still unclear whether the relative importance of biotic and abiotic variables such as plant C input and mineral properties in regulating microbial necromass C would change with soil depth. Based on the combination of large-scale sampling along a ~2200 km transect across Tibetan alpine grasslands and biomarker analysis, together with a global data synthesis across grassland ecosystems, we observed a relatively low proportion of microbial-derived C in Tibetan alpine grasslands compared to global grasslands (topsoil: 45.4% vs. 58.1%; subsoil: 41.7% vs. 53.7%). We also found that major determinants of microbial necromass C depended on soil depth. In topsoil, both plant C input and mineral protection exerted dominant effects on microbial necromass C. However, in subsoil, the physico-chemical protection provided by soil clay particles, iron-aluminum oxides, and exchangeable calcium dominantly facilitated the preservation of microbial necromass C. The differential drivers over microbial necromass C between soil depths should be considered in Earth system models for accurately forecasting soil C dynamics and its potential feedback to global warming.


Plasma sprayed hydroxyapatite coatings on titanium substrates. Part 1: Mechanical properties and residual stress levels.
Hydroxyapatite (HA) coatings have been sprayed on to substrates of Ti-6Al-4V, using a range of input power levels and plasma gas mixtures. Coatings have also been produced on substrates of mild steel and tungsten, in order to explore certain aspects of the mechanical behaviour of HA without the complication of yielding or creep in the substrate. Studies have been made of the phase constitution, porosity, degree of crystallinity, OH ion content, microstructure and surface roughness of the HA coatings. The Young's moduli in tension and in compression were evaluated by the cantilever beam bend test using a tungsten/HA composite beam. The flexural Young's modulus was determined using a free-standing deposit under the same test. Adhesion was characterised using the single-edge notch-bend test; this is considered superior to the tensile bond strength test in common use. Measured interfacial fracture energies were of the order 1-10 J m(-2). Stress levels were investigated using specimen curvature measurements in conjunction with a numerical process model. The quenching stress for HA was measured to be about 10-25 MPa and the residual stress level in HA coatings at room temperature are predicted to lie in the approximate range of 20-40 MPa (tensile). These residual stresses could be reduced in magnitude by maintaining the substrate at a low temperature (possibly below room temperature) during spraying and it may be worthwhile to explore this. Ideally, the HA coating should have low porosity, high cohesive strength, good adhesion to the substrate, a high degree of crystallinity and high chemical purity and phase stability. In practice, such combinations are rather difficult to achieve by just varying the spraying parameters.


Potential benefit of inhibitors of advanced glycation end products in the progression of type II diabetes: a study with aminoguanidine in C57/BLKsJ diabetic mice.
Prolonged hyperglycemia in type II diabetic patients is linked both with diabetic complications and with further impairment of glucose homeostasis, possibly due to glucose toxicity of the beta cell. While the connection between the accumulation of extracellular advanced glycation end products (AGEs) and the development of complications is well established, it has only recently been suggested that intracellular glycation may be equally adverse and could be involved in the pathogenesis of glucose toxicity in vitro. Aminoguanidine is a recognized inhibitor of the formation of both extracellular and intracellular AGEs. In this study, we show that the development of diabetes, measured by increased water intake and concomitant midday blood glucose levels in type II genetically diabetic mice, is reduced by treatment with aminoguanidine at a dosage of 500 mg/kg/d for 12 weeks in the diet. In addition, at the end of the study, aminoguanidine reduced the decline in serum and pancreatic insulin levels and the degree of pancreatic islet morphological degeneration, all of which are associated with pancreatic insufficiency following prolonged hyperglycemia in this animal model. These results suggest that AGEs may be involved in the aggravation of type II diabetes in vivo and aminoguanidine may be beneficial in its treatment.


Potassium-induced release of enkephalins from rat striatal slices.
The rate of release of enkephalin from rat striatal slices increased 7--10 fold in response to depolarization by 50 mM potassium ions in vitro. The potassium-evoked release of enkephalins was abolished in a calcium deficient medium. Uptake studies indicated that the potassium-stimulated efflux was not due to the inhibition of an active uptake mechanism for these peptides. These findings provide support for the view that enkephalins may function as neurotransmitters in brain.


Sepsis, resuscitated hemorrhagic shock and "shock lung:" An experimental correlation.
Dogs were submitted to hermorrhagic shock, resuscitated shock and resuscitated shock plus a pulmonary bacterial insult. Pulmonary familure was absent in dogs submitted only to shock or to shock and its resuscitation. The addition of usually sub-lethal amounts of micro-organisms to the shock-resuscitated lung caused rapid death from pulmonary failure. Pulmonary failure was demonstrated by increased lung weight, hypoxemia, decreased compliance and a hemorrhagic destruction of lung tissue. These findings strongly support recent concepts of an infective genesis of "shock lung" in man.


Osimertinib combined with bevacizumab for leptomeningeal metastasis from EGFR-mutation non-small cell lung cancer: A phase II single-arm prospective clinical trial.
Leptomeningeal metastasis (LM) is associated with poor prognosis in non-small cell lung cancer (NSCLC). The aim of this study was to investigate the efficacy and safety of osimertinib combined with bevacizumab for LM from epidermal growth factor receptor mutation (EGFRm) NSCLC. We conducted a phase II single-arm prospective clinical trial of EGFRm NSCLC with LM treated with osimertinib combined with bevacizumab. LM response assessment was based on the modified RANO LM radiological criteria; CNS and extra-CNS response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary end points included LM progression-free survival (PFS) and objective response rate (ORR); the secondary end points included safety and LM overall survival (OS). A total of 14 patients were included in the study, with a median age of 61 years, and they were predominantly female (64%). EGFR mutations were reported in exons 19 del (n = 7) and 21 L858R (n = 7). When LM was diagnosed, 12 (85.7%) patients had clinical symptoms, 71.4% (10/14) of patients were diagnosed with LM by cytology, and five (35.7%) patients had a performance status (PS) score > 2. The median LM PFS was 9.3 months (95% CI: 8.2-10.4), and the LM ORR was 50%. The safety findings in the present study were consistent with the known profile of osimertinib with bevacizumab; the median LM OS was 12.6 months, and the one-year survival rate was 35.7%. Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC. SIGNIFICANT FINDINGS OF THE STUDY: To date, there is no prospective clinical study on the treatment of osimertinib combined with bevacizumab in EGFRm NSCLC with LM. The median LM PFS was 9.3 months (95% CI: 8.2-10.4), and the LM ORR was 50%, the median LM OS was 12.6 months, and the one-year survival rate was 35.7%. Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC.


Immunocytochemical localization of ubiquitin at human neuromuscular junctions.
Using several specific monoclonal and polyclonal antibodies, we found that ubiquitin is highly concentrated in the post-synaptic domain of human neuromuscular junctions. The distribution and pattern of ubiquitin immunoreactivity is identical to the localization of bound alpha-bungarotoxin, suggesting that ubiquitin may be involved in post-translational modification or turnover of the acetylcholine receptor or other junctional proteins of the muscle fibre.


Anterior urethral valve associated with posterior urethral valves.
The association of anterior urethral valve (AUV) with posterior urethral valve (PUV) is rare. A 7-month-old infant was presented at a district hospital with episodes of acute pyelonephritis. He was treated medically and a voiding cystourethrogram (VCUG) confirmed bilateral vesico-urethral reflux. The presence of concomitant AUV and PUV was not recognized. He underwent several surgical procedures, which failed. He had reflux recurrence following two antireflux procedures. He had urinary retention after each operation, which was managed by vesicostomy and perineal urethrostomy. At the age of 3.5 years, he was referred to our paediatric urology clinic. Noticing the AUV and PUV in the past VCUG, the valves were fulgurated. Urodynamic study before and 3 months after valve ablation showed a high voiding pressure. VCUG 6 months following ablation showed no reflux, but several uroflowmetric studies showed a staccato and interrupted pattern. Empirical treatment with an alpha-blocker was started. One year after treatment, a repeat VCUG showed no reflux. Uroflowmetry and urodynamic studies returned to normal. The perineal urethrostomy was closed. The child was asymptomatic after 9 months of follow up.


Effects of growth differentiation factor 8 on steroidogenesis in human granulosa-lutein cells.
To investigate the biological role of growth differentiation factor 8 (GDF8) in the regulation of steroidogenesis in human granulosa-lutein (hGL) cells. Experimental study. Academic medical center. In vitro fertilization patients who provided hGL cells. Cultured hGL cells treated with recombinant human GDF8 for 24 hours. Expression of steroidogenic enzymes and steroid production in primary cultures of hGL cells used to investigate the effects of GDF8 via specific mRNA and protein levels examined using real time-quantitative polymerase chain reaction and Western blot analysis, respectively, and levels of estradiol and progesterone measured by enzyme immunoassays. Extracts were prepared from cultured hGL cells after exposure to GDF8. The levels of cytochrome P450 aromatase (aromatase), the FSH receptor, and estradiol were increased, whereas steroidogenic acute regulatory protein (StAR), luteinizing hormone (LH) receptor, and progesterone levels were decreased after treatment with GDF8. In addition, follicle-stimulating hormone (FSH) stimulated the production of aromatase/estradiol, and LH induced the production of StAR/progesterone. Furthermore, pretreatment with GDF8 for 24 hours enhanced the effects of FSH on aromatase/estradiol induction, whereas GDF8 suppressed the effects of LH on StAR/progesterone stimulation. In human granulosa cells, GDF8 may play an important role in the modulation of cellular responsiveness to gonadotropins and in the regulation of ovarian steroid production, most likely as a luteinization inhibitor.


Pilot study of neuraxial imaging by ultrasound in infants and children.
Ultrasonography is becoming an important adjunct in regional anesthesia. Epidural anesthesia may pose significant challenges in infants and children because of difficulties in identifying the epidural space. In addition, epidural catheters are sometimes difficult to advance. The present study was performed to evaluate an optimal ultrasound technique for direct visualization of neuraxial structures in children. A total of 32 infants and children scheduled for minor surgery were prospectively included in a high-resolution ultrasound study. Scans were performed using either a sector or linear probe and views from a longitudinal paramedian, median and transversal angle at lumbar and thoracic levels of the spinal cord were analyzed. In all children investigated, the linear probe generated better images than the sector probe. Of the various scanning perspectives, the paramedian longitudinal approach offered the best views at both cord levels. Broken down by age groups, the best visibility was clearly obtained in neonates up to 3 months of age (P < 0.0001 Vs all other age groups). In older children, the quality of ultrasound decreased in an age-dependent manner. Paramedian longitudinal scans with linear probes are the most favorable method of imaging neuraxial anatomy at lumbar and thoracic cord levels in infants and children, with the best results in neonates up to 3 months of age. Based on these results, and using real time imaging, a practical technique for ultrasound-guided epidural anesthesia for neonates and infants at lumbar and thoracic levels of the spinal cord is planned.


[Diagnostic quality of transluminal biopsy in undetermined biliary duct stenosis by primary PTCD with "cross and push" technique - a prospective monocentric pilot study].
Histological characterisation of a biliary duct stenosis can be essential for further therapeutic steps. Access to the stenosis is not given in every patient by endoscopic retrograde cholangiography. In these cases, a percutaneous transhepatic cholangiodrainage (PTCD) may be helpful. The optimal preparation and diagnostic precision of taking a biopsy by PTCD is not sufficiently evaluated. After a training phase of 10 patients, PTCDs in 30 patients with a biliary duct stenosis and lack of adequate drainage by ERC were done in a time range of 24 months. The stenosis was passed with a wire and then a directed forceps-biopsy was performed in a "cross and push" technique (Transluminal Biliary Biopsy Forceps Set, Cook Medical™), using a wire-guided introducer (7 Fr. inner diameter). The result of the histological survey was then correlated with the definite diagnosis. The follow-up time was 18 months. Out of 30 patients, there were 22 (73 %) with a malignant stenosis (10 biliary duct neoplasms, 12 non-biliary carcinoma/metastases/lymphomas). Eight (27 %) out of 30 patients had a benign stenosis. In case of all 30 patients, there was enough tissue gained by biopsy for histologic survey. Sub-group analysis was performed for biliary duct cancer and non-biliary cancer. Thereby, 8 out of 10 patients with biliary duct neoplasms were also classified as malignant by histology (sensitivity 80 %); whereas, only 8 out of 12 non-biliary cancers could be histologically classified as malignant (sensitivity 66.6 %, difference not significant, p = 0.0577). In all patients with benign stenosis, histological evaluation of biopsies revealed benign histology (specificity 100 %). There were no intervention-related complications. This prospective cohort-study shows a high diagnostic precision for the percutaneous transductal biopsy-set to evaluate an undetermined biliary duct stenosis-particularly in biliary processes. Because it can be difficult to gain histology in malignant biliary duct processes using different methods, the "cross and push" biopsy completes the spectrum of diagnostic procedures.


Radiographic and microscopic evaluation of subperiosteally implanted blocks of hydrated and hardened alpha-tricalcium phosphate in rabbits.
Tissue response to preformed tricalcium phosphate (TCP) blocks prepared from alpha-tricalcium phosphate (alpha-TCP) powder by hydration and hardening at 80 degrees C was studied by implanting them subperiosteally on the buccal aspect of the mandible in rabbits. X-ray diffraction of the alpha-TCP powder showed a typical pattern of TCP, whereas a mixed pattern of TCP and hydroxylapatite was obtained after hydration and hardening. The radiographic findings at 4 weeks showed a tendency to bony union of the TCP block with the underlying bone. Microscopically, new bone that was being formed extensively from the underlying bone surface and filling the space between the block and bone at 4 weeks gradually changed into lamellar bone. There was no evidence of resorption of the TCP block throughout the experiment. The tissue response was essentially consistent with that to hydroxylapatite particles studied under similar conditions in our laboratory. It was concluded that the hydration and hardening of alpha-TCP powder may provide an implant block with a desirable contour that does not interfere with bone formation.


Induction of crassulacean acid metabolism in Mesembryanthemum crystallinum increases reproductive success under conditions of drought and salinity stress.
Mesembryanthemum crystallinum L., an inducible crassulacean acid metabolism (CAM) plant, was grown for approximately 5 weeks following germination in well-watered, non-saline soil in a controlled-environment chamber. During this time, plants were characterized by C3 photosynthetic carbon metabolism. After the initial 5 weeks, CAM was induced by a combination of high soil salinity and reduced soil water content. One group of plants was allowed to engage in CAM by being continuously exposed to normal CO2-containing air (about 350-400 ppm). A second group of plants was deprived of ambient CO2 each night (12 h dark period) until completion of their life cycle, thereby minimizing potential carbon gain via dark CO2 fixation. The capacity to express CAM under conditions of drought and salinity stress markedly improved reproductive success: plants kept in normal CO2-containing air produced about 10 times more seeds than plants kept in CO2-free air during dark periods. Seeds from plants deprived of ambient CO2 overnight had more negative δ13C values than seeds from plants kept in normal air.


Bilateral chylothorax: A late complication of Kawashima procedure despite normal pulmonary pressures.
Chylothorax, a relatively rare congenital heart disease early postoperative complication, is occurring more frequently due to complexity of cardiac surgeries. We present a 9-month-old boy who had hypoplastic left heart (HLH) syndrome with interrupted inferior vena cava (IVC) and bilateral superior vena cava (SVC) palliated with left sided modified Blalock-Taussig (MBT) shunt during neonatal period and second stage palliation with left sided bidirectional glen (BDG) procedure and right sided Kawashima procedure develop bilateral chylothorax two weeks after discharge. This is the first reported case in the literature of a patient who developed chylothorax with relatively low Fontan systemic venous pressures after a Kawashima procedure. Clinically important chylothorax may be a marker of poor long-term outcomes, demonstrating an inability to handle overwhelming lymphatic congestion. Early diagnosis of chylothorax in complex cardiac surgeries may permit successful conservative management.


Parental smoking and respiratory illnesses in Australian children aged 0-4 years: ABS 1989-90 National Health Survey results.
This study investigated the associations between parental smoking and respiratory infections in Australian children aged 0-4 years. Data from the ABS 1989-90 National Health Survey were used. The exposure variables examined were maternal, paternal and combined family smoking. Outcome variables were parent-reported chronic or recent asthma, asthma wheeze, bronchitis, influenza, common cold, cough, otitis media and other respiratory conditions. Logistic regression techniques were used to control for confounding by socio-economic status, child's sex, maternal education, place of residence, ethnicity and family size. Of the 4,281 children in the sample, 45% lived in households with one or more current smokers and 29% had a mother who smoked. Maternal (but not paternal) smoking was significantly associated with asthma (OR 1.52, 95% CI 1.19-1.94) and asthma wheeze (OR 1.51, 95% CI 1.26-1.80). No other significant associations were observed. Positive and significant dose response relationships were found between the amount of maternal smoking and both asthma variables. Population attributable risks were calculated and almost 13% of asthma and asthma wheeze in 0-4 year old Australian children in 1989-90 was estimated to be due to maternal smoking. Large numbers of Australian children live in households with smokers. This study, like others, has shown an association between maternal smoking and respiratory illnesses in young children. Further strategies are needed to prevent or reduce young children's exposure to environmental tobacco smoke in their homes.


The Rb/E2F axis is a key regulator of the molecular signatures instructing the quiescent and activated adult neural stem cell state.
Long-term maintenance of the adult neurogenic niche depends on proper regulation of entry and exit from quiescence. Neural stem cell (NSC) transition from quiescence to activation is a complex process requiring precise cell-cycle control coordinated with transcriptional and morphological changes. How NSC fate transitions in coordination with the cell-cycle machinery remains poorly understood. Here we show that the Rb/E2F axis functions by linking the cell-cycle machinery to pivotal regulators of NSC fate. Deletion of Rb family proteins results in activation of NSCs, inducing a transcriptomic transition toward activation. Deletion of their target activator E2Fs1/3 results in intractable quiescence and cessation of neurogenesis. We show that the Rb/E2F axis mediates these fate transitions through regulation of factors essential for NSC function, including REST and ASCL1. Thus, the Rb/E2F axis is an important regulator of NSC fate, coordinating cell-cycle control with NSC activation and quiescence fate transitions.


Deoxyguanosine reverses inhibition by hydroxyurea of repair of UV-irradiated adenovirus 5.
Hydroxyurea, an inhibitor of ribonucleotide reductase, blocks the repair by normal human fibroblasts of ultraviolet light-damaged adenovirus 5. A mixture of all four DNA deoxynucleosides present with hydroxyurea reversed the inhibition, an effect consistent with the target of hydroxyurea being ribonucleotide reductase. Single deoxynucleosides were differentially effective in reversing the inhibition: deoxyguanosine reversed 100% of the HU block, deoxyadenosine 70%, deoxythymidine 55%, but deoxycytidine only 3%. The results are interpreted in the context of the known pattern of stimulation and inhibition of mammalian ribonucleotide reductase by dNTP effectors. We suggest that biological data may be important to assessing the availability of substrate for the ribonucleotide reductase molecules that provide dNTPs for DNA repair.


A Laboratory-Based Study of the Priming Effects of Food Cues and Stress on Hunger and Food Intake in Individuals with Obesity.
This study aimed to assess the effects of exposures to food cues and stress on hunger and food intake and examine whether cue responses differ by weight status. In a laboratory-based experimental study, participants (n = 138) were exposed to stress, neutral, and food cues delivered using an individualized script-driven imagery task on three separate days. After each cue exposure, participants ate high- and low-calorie snack foods ad libitum (Food Snack Test). Hunger was measured by visual analog scales. Food cues elicited significantly greater increases in hunger compared with neutral and stress stimuli. Cue-induced hunger did not differ by weight status. Participants consumed a similar number of total calories across stimuli. In response to food cue provocation, participants with obesity consumed [mean (SE)] 81.0% (4.0%) of calories from high-calorie foods, which was significantly greater than participants with normal weight (63.5% [3.6%]; P = 0.001). After the stress cue, participants with obesity consumed 81.4% (4.0%) of calories from high-calorie foods, which was significantly more than participants with normal weight (70.2% [3.6%]; P = 0.04). Energy intake from high-calorie foods did not differ by weight status after the neutral cue. Among individuals with obesity, exposure to food and stress cues shifted consumption to high-calorie snack foods within a well-controlled experimental setting.


Antibodies from patients with melioidosis recognize Burkholderia mallei but not Burkholderia thailandensis antigens in the indirect hemagglutination assay.
The indirect hemagglutination assay routinely used to detect antibodies to Burkholderia pseudomallei was modified to detect cross-reactivity of antibodies to B. pseudomallei, B. mallei, and B. thailandensis antigens. We demonstrate a lack of cross-reactivity between B. pseudomallei and B. thailandensis but marked cross-reactivity between B. pseudomallei and B. mallei.


ANGIOGRAPHIC SMOKESTACK LEAKAGE NOT ASSOCIATED WITH CENTRAL SEROUS CHORIORETINOPATHY.
To report a series of cases with smokestack leakage on fundus fluorescein angiography outside the clinical setting of central serous chorioretinopathy. A multicenter, observational retrospective case series evaluating fundus fluorescein angiography on Topcon and Optos systems. Seven patients with neovascularization due to ischemic retinopathy demonstrated a unique smokestack pattern of angiographic leakage. The patients' ages ranged between 44 and 71 years and were seen at 3 academic teaching hospitals in the Washington-Baltimore metropolitan area. Five patients had been diagnosed with proliferative diabetic retinopathy, one with sickle cell ischemic retinopathy, and one with branch retinal artery occlusion; none of the patients had a known history or clinical signs of current or past central serous chorioretinopathy. This is the first published case series to the author's knowledge of ischemic retinopathy displaying a smokestack leakage pattern on fundus fluorescein angiography that is classically described with idiopathic central serous chorioretinopathy.


Glycosylation Quality Control by the Golgi Structure.
Glycosylation is a ubiquitous modification that occurs on proteins and lipids in all living cells. Consistent with their high complexity, glycans play crucial biological roles in protein quality control and recognition events. Asparagine-linked protein N-glycosylation, the most complex glycosylation, initiates in the endoplasmic reticulum and matures in the Golgi apparatus. This process not only requires an accurate distribution of processing machineries, such as glycosyltransferases, glycosidases, and nucleotide sugar transporters, but also needs an efficient and well-organized factory that is responsible for the fidelity and quality control of sugar chain processing. In addition, accurate glycosylation must occur in coordination with protein trafficking and sorting. These activities are carried out by the Golgi apparatus, a membrane organelle in the center of the secretory pathway. To accomplish these tasks, the Golgi has developed into a unique stacked structure of closely aligned, flattened cisternae in which Golgi enzymes reside; in mammalian cells, dozens of Golgi stacks are often laterally linked into a ribbon-like structure. Here, we review our current knowledge of how the Golgi structure is formed and why its formation is required for accurate glycosylation, with the focus on how the Golgi stacking factors GRASP55 and GRASP65 generate the Golgi structure and how the conserved oligomeric Golgi complex maintains Golgi enzymes in different Golgi subcompartments by retrograde protein trafficking.


PIK3CA mutation analysis in Chinese patients with surgically resected cervical cancer.
The aim of this study was to evaluate the clinicopathological and prognostic relevance of PIK3CA mutations in Chinese patients with surgically resected cervical cancer. PIK3CA mutations were screened in 771 cervical cancer specimens using reverse transcription polymerase chain reaction and Sanger sequencing. In total, 13.6% (105 of 771) of patients harbored non-synonymous PIK3CA mutations. Patients harboring PIK3CA mutations were older than patients with wild-type PIK3CA (mean age: 50.7 years vs. 47.0 years, P < 0.01). PIK3CA mutations were more commonly observed in postmenopausal patients than in premenopausal patients (19.6% vs. 10.2%, P < 0.01). PIK3CA mutations were more common in squamous cell carcinomas than in non-squamous cell tumors (15.3% vs 7.3%, of P < 0.01). The 3-year relapse-free survival was 90.2% for PIK3CA mutant patients and 80.9% for PIK3CA wild-type patients (P = 0.03). PIK3CA mutation was confirmed as an independent predictor for better treatment outcome in the multivariate analyses (HR = 0.54, 95% CI: 0.29-0.99, P = 0.048). PIK3CA mutations were significantly associated with less distant metastases (mutant-type: 8/105, wild-type: 98/666, p = 0.048). Thus, patients with mutant PIK3CA had distinct characteristics in age, menopausal status, and histological subtype and have better treatment outcome and less distant metastasis after surgery-based multimodal therapy.


Impact of COVID-19 lockdown policy on homicide, suicide, and motor vehicle deaths in Peru.
Although lockdown measures to stop COVID-19 have direct effects on disease transmission, their impact on violent and accidental deaths remains unknown. Our study aims to assess the early impact of COVID-19 lockdown on violent and accidental deaths in Peru. Based on data from the Peruvian National Death Information System, an interrupted time series analysis was performed to assess the immediate impact and change in the trend of COVID-19 lockdown on external causes of death including homicide, suicide, and traffic accidents. The analysis was stratified by sex and the time unit was every 15 days. All forms of deaths examined presented a sudden drop after the lockdown. The biggest drop was in deaths related to traffic accidents, with a reduction of 12.22 deaths per million men per month (95% CI: -14.45, -9.98) and 3.55 deaths per million women per month (95% CI:-4.81, -2.30). Homicide and suicide presented similar level drop in women, while the homicide reduction was 2.5 the size of the suicide reduction in men. The slope in homicide in men during the lock-down period increased by 6.66 deaths per million men per year (95% CI:3.18, 10.15). External deaths presented a sudden drop after the lockdown was implemented and an increase in homicide in men was observed. Falls in mobility have a natural impact on traffic accidents, however, the patterns for suicide and homicide are less intuitive and reveal important characteristics of these events, although we expect all of these changes to be transient.


Sulfation of the FLAG epitope is affected by co-expression of G protein-coupled receptors in a mammalian cell model.
G protein-coupled receptors (GPCRs) are important therapeutic targets and therefore extensively studied. Like most transmembrane proteins, there has been considerable difficulty in developing reliable specific antibodies for them. To overcome this, epitope tags are often used to facilitate antibody recognition in studies on fundamental receptor signalling and trafficking. In our study of cannabinoid CB1/dopamine D2 interactions we sought to generate HEK293 cells expressing FLAG-tagged D2 for use in antibody-based assays of GPCR localisation and trafficking activity, however observed that stable FLAG-hD2 expression was particularly challenging to maintain. In contrast, when expressed in cell lines expressing hCB1 robust and stable FLAG-hD2 expression was observed. We hypothesised that co-expression of CB1 might stabilise surface FLAG-hD2 expression, and therefore investigated this further. Here, we describe the observation that co-expression of either cannabinoid CB1 or CB2 receptors in HEK293 decreases the sulfation of a FLAG epitope appended at the N-terminus of the dopamine D2 receptor. Sulfation alters epitope recognition by some anti-FLAG antibodies, leading to the detection of fewer receptors, even though expression is maintained. This demonstrates that cannabinoid receptor expression modifies posttranslational processing of the FLAG-hD2 receptor, and importantly, has wider implications for the utilisation and interpretation of receptor studies involving epitope tags.


Mechanistic Insights of the Critical Role of Hydrogen Donor in Controlling Drug Release From Acrylate Adhesive.
In the present study, a pyrrolidone adhesive and an amide adhesive were synthesized, and their molecular mechanisms of controlled drug release were described. Using zolmitriptan as model drug, in vitro drug release and skin permeation experiments were performed. Adhesive properties were evaluated using modulated differential scanning calorimetry and rheology study. Free volume of polymer was directly obtained by positron annihilation lifetime spectroscopy. Intermolecular interactions between drugs and adhesives were determined by FTIR spectroscopic analysis and molecular simulation. Release percent (24 h) of zolmitriptan from pyrrolidone adhesive was about 55.8 ± 3.1% (w/w), while from amide adhesive, the release percent (24 h) was about 40.1 ± 1.6% (w/w). The free volume sizes of pyrrolidone adhesive and amide adhesive were about 2309.6 Å3 and 2854.5 Å3, respectively, which were much larger than molecular volume of zolmitriptan (about 285.7 Å3). Thus, the polymer networks might not hinder drug diffusion from the view of free volume. Comparing chemical structures of pyrrolidone group and primary amide group, the main difference was that primary amide group of amide adhesive possessed 2 hydrogen donors. It was proved that hydrogen bonding between zolmitriptan and hydrogen donor of primary amide group played a critical role in controlling drug release.


Simultaneous enrichment and determination of cadmium and mercury ions using magnetic PAMAM dendrimers as the adsorbents for magnetic solid phase extraction coupled with high performance liquid chromatography.
In present study, a sensitive and efficient method based on magnetic PAMAM dendrimers as the sorbents for magnetic solid-phase extraction (MSPE) coupled with high performance liquid-phase chromatography and ultraviolet variable wavelength detector (HPLC-VWD) was developed for simultaneous determination of trace cadmium and mercury ions. Sodium diethyldithiocarbamate (DDTC-Na) was used as the chelating agent during the elution process. Parameters that would affect the extraction efficiency including PAMAM generation, adsorbent dosage, adsorption time, elution time and volume, pH and coexisting ions were investigated to achieve the best adsorption efficiency. Under the optimal conditions, good linear relationship was obtained in the range of 0.05-200 μg L-1 for Cd2+ and 0.1-200 μg L-1 for Hg2+, and the limits of detection were 0.016 and 0.040 μg L-1, respectively. The spiked recoveries of Cd2+ and Hg2+ were satisfied in the range of 91.5-105% (n = 3). The proposed method was proved to be an alternative and reliable method to determine trace Cd2+ and Hg2+ in water samples.


Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis.
Twenty-four-hour trough (R)- and (R,S)-methadone plasma concentrations were measured on 94 methadone maintenance treatment (MMT) patients classified as 'responders' or 'non-responders', based on urine toxicology evidence of recent illicit opiate use. Receiver operating characteristic (ROC) curves for daily dose, dose/bodyweight, and (R)- and (R,S)-methadone trough plasma concentrations were used to identify optimal thresholds; areas under the curve (AUC) were used to compare predictive power. Non-responders (n=37) had a lower mean dose (73 mg/day versus 147 mg/day; p<0.001), (R)-methadone concentration (136 ng/ml versus 223 ng/ml; p<0.005) and (R,S)-methadone concentration (266 ng/ml versus 409 ng/ml; p=0.001) than responders. On multivariate regression, duration of treatment and methadone dose were significantly associated with treatment response. After backward stepwise regression, each year of treatment increased the odds of abstinence from illicit opioid use by 34% (OR 1.34; 95% CI 1.14-1.57)); each 20mg of methadone dose by 36% (OR 1.36 CI; 95% CI 1.11-1.67). On ROC analysis, AUC for daily dose (0.77, 95% CI 0.68-0.87), dose/bodyweight (0.76, 95% CI 0.66-0.85), (R)-methadone (0.73, 95% CI 0.63-0.84) and (R,S)-methadone concentration (0.70, 95% CI 0.59-0.81) did not differ significantly. Dose/bodyweight, and trough plasma concentrations of (R)- or (R,S)-methadone were no better predictors of treatment response than daily dose, and did not improve the fit of the model for treatment outcome as judged by the likelihood ratio test (p=0.21, 0.88, and 0.97, respectively). Optimal therapeutic thresholds (sensitivity, specificity) were: daily dose 100mg/day (67%, 81%); (R)-methadone 200 ng/ml (51%, 78%); (R,S)-methadone 400 ng/ml (40%, 81%). Thresholds with specificity near 90% (dose 140 mg/day; (R)-methadone 250 ng/ml; (R,S)-methadone 500 ng/ml) may help guide dose titration for patients continuing to use illicit opiates.


Concentration of free amino acids in human milk of women with gestational diabetes mellitus and healthy women.
It is generally agreed that breastfeeding has a positive effect on the metabolic situation in diabetic mothers. However, negative long-term effects are described for breastfed offspring of diabetic women. It is unknown if the composition of free amino acids (FAAs) in breastmilk of women with gestational diabetes mellitus (GDM) differs from that in milk of healthy women. We studied the amount of FAAs in breastmilk of women with GDM and women with normal glucose tolerance (NGT). Human milk samples of 68 women (21 GDM and 47 NGT) were analyzed. Contents of FAAs in milk samples, obtained within the first 4 days after delivery (colostrum) and 6 weeks later (mature milk), were analyzed using high-performance liquid chromatography. Total amounts of FAAs in colostrum and in mature milk were compared between the groups. The impact of maternal age, body mass index (BMI), gestational age at birth, birth weight, and diagnosis of GDM on the total amount of FAAs was evaluated. Overall, the total amount of FAAs increased significantly from colostrum to mature milk in both groups (p<0.001). The total amount of FAAs did not significantly differ between GDM and NGT in colostrum and in mature milk (1,560 μmol/L vs. 1,730 μmol/L and 2,440 μmol/L vs. 2,723 μmol/L, respectively). No significant influence on the total amount of FAAs at both measurements of maternal age, BMI, gestational age at birth, birth weight, and diagnosis of GDM could be observed by regression analyses. The content of FAAs of human milk does not significantly differ between women with GDM and women with NGT.


Application of a novel prognostic invasive lesion index in ductal carcinoma in situ with minimal invasion of the breast.
Multiple invasive foci has been shown to increase the risk of lymph node metastasis (LNM) in early breast cancer, but its prognostic implication remains unknown. We aimed to identify the prognostic value of the number of invasive foci in ductal carcinoma in situ with minimal invasion of the breast (DCIS-MI), and further establish a prognostic invasive lesion index (ILI). A total of 193 patients with DCIS-MI (the invasive component was up to 10 mm in diameter) were included. Univariate and multivariate analysis (logistic regression) were used to evaluate the predictive value of the number of invasive foci in LNM. The Kaplan-Meier curve was used for survival analysis. More than five invasive foci was an independent predictor for LNM (OR, 2.67, 95% CI, 1.12-6.33, P = 0.026), and associated with significantly shorter disease-free survival (DFS) and overall survival (OS) compared with no more than five invasive foci (mean DFS 123.8 vs. 148.0 months, P = 0.002; and mean OS 133.5 vs. 151.4 months, P = 0.025). The ILI was established by the sum scores of the number of invasive foci and the invasive component size, having an optimal cut-off point of 5.5 scores. The high-ILI group (ILI >5 scores) had a higher incidence of LNM (23.6% vs. 6.9%) and worse prognosis than the low-ILI group (ILI ≤5 scores). In conclusion, more than five invasive foci was an independent predictor for LNM and an unfavorable prognostic parameter. The ILI could potentially be used to predict survival prognosis in patients with DCIS-MI.


Fatty acid oxidation in rat brain is limited by the low activity of 3-ketoacyl-coenzyme A thiolase.
In an attempt to clarify why the brain oxidizes fatty acids poorly or not at all, the activities of beta-oxidation enzymes present in rat brain and rat heart mitochondria were measured and compared with each other. Although the apparent Km values and chain-length specificities of the brain and heart enzymes are similar, the specific activities of all but one brain enzyme are between 4 and 50% of those observed in heart mitochondria. The exception is 3-ketoacyl-CoA thiolase (EC 188.8.131.52) whose specific activity in brain mitochondria is 125 times lower than in heart mitochondria. The partially purified brain 3-ketoacyl-CoA thiolase was shown to be catalytically and immunologically identical with the heart enzyme. The low rate of fatty acid oxidation in brain mitochondria, estimated on the basis of palmitoylcarnitine-supported respiration and [1-14C]palmitoylcarnitine degradation to be less than 0.5 nmol/min/mg of protein, may be the consequence of the low activity of 3-ketoacyl-CoA thiolase. Inhibition of [1-14C]palmitoylcarnitine oxidation by 4-bromocrotonic acid proves the observed oxidation of fatty acids in brain to be dependent on 3-ketoacyl-CoA thiolase and thus to occur via beta-oxidation. Since the reactions catalyzed by carnitine palmitoyltransferase (EC 22.214.171.124) and acyl-CoA synthetase (EC 188.8.131.52) do not seem to restrict fatty acid oxidation in brain, it is concluded that the oxidation of fatty acids in rat brain is limited by the activity of the mitochondrial 3-keto-acyl-CoA thiolase.


NeuroD induces the expression of visinin and calretinin by proliferating cells derived from toxin-damaged chicken retina.
Müller glia have been shown to be a potential source of neural regeneration in the avian retina. In response to acute damage Müller glia de-differentiate, proliferate, express transcription factors found in embryonic retinal progenitors, and some of the progeny differentiate into neurons and glia (Fischer and Reh [2001a] Nat. Neurosci. 4:247-252). However, most of the cells produced by proliferating Müller cells appear to remain undifferentiated. The purpose of this study was to test whether the neurogenic gene NeuroD can promote the differentiation of proliferating cells derived from the postnatal chick retina. We used recombinant avian retroviruses to transfect green fluorescent protein (GFP) or NeuroD. The majority of cells transfected with GFP remained undifferentiated, with a few cells differentiating into calretinin-immunoreactive neurons. Many cells transfected with the NeuroD-virus expressed calretinin, neurofilament, or visinin, while most cells remained undifferentiated. The number of calretinin-expressing cells that were generated was increased approximately 20-fold with forced expression of NeuroD. In addition, we found that cells transfected with NeuroD never expressed glutamine synthetase, a marker of mature Müller glia, suggesting that NeuroD suppresses glial differentiation. We conclude that NeuroD stimulates cells from the toxin-damaged chicken retina to acquire some neuronal phenotypes. We propose that most of these cells were derived from Müller glia.


Comparison between clinical diagnosis and CSF biomarkers of Alzheimer disease in elderly patients with late onset psychosis: Helsinki Old Age Psychosis Study (HOPS).
To determine the proportion of elderly people with a first psychotic episode actually suffering from dementia, especially Alzheimer disease (AD), by using cerebrospinal fluid (CSF) biomarkers. Prospective case-control study. Sixty-six patients age 65 years and older with recent psychotic symptoms and 12 comparison subjects with chronic schizophrenia over 10 years that were referred to acute old age psychiatry, in-ward treatment. Concentration levels of CSF Aβ42, tau and p-tau-181 measured by ELISA compared to clinical diagnosis made by a multiprofessional team of one neurologist and several psychiatrists. The CSF specimen was obtained from 51 (65.4%) of the patients. In five subjects out of 13 with a clinical diagnosis of AD, all the CSF biomarkers (Aβ42, tau and p-tau) were normal. Only one patient out of 25 with a psychiatric diagnosis and none out of the comparison group with schizophrenia showed a CSF profile typical of AD. Three patients with an AD diagnosis, four patients with a psychiatric diagnosis and one patient with schizophrenia had a low Aβ42 concentration with normal levels of tau or p-tau. The patients with AD had lower CSF Aβ42 levels than other patients. The CSF biomarkers are important and useful as part of the diagnostic procedure for detecting AD and other dementia in elderly patients displaying psychotic symptoms. The accuracy of AD diagnosis encounters problems due to atypical behavioural symptoms in psychiatric settings and thus the differential diagnostics can be improved by using CSF biomarkers of AD more frequently.


Silver nanoparticle-based SERS sensors for sensitive detection of amyloid-β aggregates in biological fluids.
One of the hallmarks of Alzheimer's disease (AD) pathogenesis is the production, aggregation, and deposition of amyloid-β (Aβ) peptide. Surface-enhanced Raman spectroscopy (SERS) is a promising analytical technique capable of providing valuable information on chemical composition and molecule conformations in biological samples. However, one of the main challenges for introducing the SERS technique into the practice is preparation of scalable and at the same time stable nanostructured sensors with uniform spatial distribution of nanoparticles. Herein, we propose SERS platforms for reproducible, sensitive, label-free quantification of amyloid-β aggregates for short-wavelength - 532 and 633 nm - lasers. A SERS sensor - based on silver nanoparticles immobilized into a chitosan film (AgNP/CS) - provided a uniform distribution of AgNPs from a colloidal suspension across the SERS sensor, resulting in nanomolar limits of detection (LODs) for Aβ42 aggregates with a portable 532 nm laser. The laser-induced deposition was used to obtain denser periodic plasmonic sensors (AgNP/LID) with a uniform nanoparticle distribution. The AgNP/LID SERS sensor allowed for 15 pM LOD for Aβ42 aggregates with 633 nm laser. Notably, both nanostructured substrates allowed to distinguish amyloid aggregates from monomers. Therefore, our approach demonstrated applicability of SERS for detection of macromolecular volumetric objects as amyloid-β aggregates for fundamental biological studies as well as for "point-of-care" diagnostics and screening for early stages of neurodegenerative diseases.


Cochlear hair cell loss in ears with cholesteatomas. Scanning electron microscopy study.
Cochleas from 16 Mongolian gerbils with spontaneous aural cholesteatomas, and four of similar age without cholesteatomas, were examined by scanning electron microscopy to quantify cochlear hair cell loss. Loss of hair cell stereocilia was found in all ears with cholesteatomas and was significantly increased when compared with uninvolved ears from animals of similar age. The hair cell loss associated with gerbilline cholesteatomas appeared to be most marked in the middle turn of the cochlea and increased in severity with increasing size of the cholesteatomas. Outer hair cells were affected more than inner hair cells. Inner and outer hair cell loss was not significantly different in infected cholesteatomas versus sterile cholesteatomas. The greater damage to hair cells at the middle turn compared to the basal turn suggests that these losses may be the result of some agent acting through the cochlear wall rather than through the round window.


Vulvar Carcinosarcoma Composed of Intestinal-type Mucinous Adenocarcinoma Associated With Anaplastic Pleomorphic and Spindle Cell Carcinoma and Heterologous Chondrosarcomatous and Osteosarcomatous Elements: A Case Report and Review of the Literature.
Carcinosarcomas (CS) are exceedingly rare in the vulva, with only 3 cases reported in the English literature, associated with squamous cell carcinoma (2) or spiradenocarcinoma (1). We first report a vulvar CS with intestinal-type mucinous adenocarcinoma associated with anaplastic pleomorphic and spindle cell carcinoma and heterologous chondro- and osteosarcomatous elements in a 62-year-old woman, who presented with a painless, slow-growing vulvar cyst for almost 2 years, that rapidly enlarged and hardened in the last 4 months forming a mass. The tumor was widely excised, but recurred 2 months later, and she died 2 months after recurrence. A review on this entity is performed highlighting its morphologic and immunohistochemical features, and discussing issues in nomenclature and potential origins within the vulva.


Complex effects of ryanodine on the sarcoplasmic reticulum Ca2+ levels in smooth muscle cells.
We have studied the effects of ryanodine and inhibition of the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) with thapsigargin, on both [Ca(2+)](i) and the sarcoplasmic reticulum (SR) Ca(2+) level during caffeine-induced Ca(2+) release in single smooth muscle cells. Incubation with 10 microM ryanodine did not inhibit the first caffeine-induced [Ca(2+)](i) response, although it abolished the [Ca(2+)](i) response to a second application of caffeine. To assess whether ryanodine was inducing a permanent depletion of the internal Ca(2+) stores, we measured the SR Ca(2+) level with Mag-Fura-2. The magnitude of the caffeine-induced reduction in the SR Ca(2+) level was not augmented by incubating cells with 1 microM ryanodine. Moreover, on removal of caffeine, the SR Ca(2+) levels partially recovered in 61% of the cells due to the activity of thapsigargin-sensitive SERCA pumps. Unexpectedly, 10 microM ryanodine instead of inducing complete depletion of SR Ca(2+) stores markedly reduced the caffeine-induced SR Ca(2+) response. It was necessary to previously inhibit SERCA pumps with thapsigargin for ryanodine to be able to induce caffeine-triggered permanent depletion of SR Ca(2+) stores. These data suggest that the effect of ryanodine on smooth muscle SR Ca(2+) stores was markedly affected by the activity of SERCA pumps. Our data highlight the importance of directly measuring SR Ca(2+) levels to determine the effect of ryanodine on the internal Ca(2+) stores.


Importance and implications of exosomes in nephrology and urology.
Exosomes are extracellular vesicles that are formed by two invaginations of the plasma membrane and can be released by all eukaryotic cells. Because of their bioactive contents, including nucleic acids and proteins, exosomes can activate a variety of functions in their recipient cells. Due to the plethora of physiological and pathophysiological functions, exosomes have received a lot of attention from researchers over the past few years. However, there is still no consensus regarding isolation and characterization protocols of exosomes and their subtypes. This heterogeneity poses a lot of methodical challenges but also offers new clinical opportunities simultaneously. So far, exosome-based research is still mostly limited to preclinical experiments and early-stage clinical trials since the translation of experimental findings remains difficult. Exosomes could potentially play an important role as future diagnostic and prognostic agents and might also be part of the development of new treatment strategies. Therefore, they have previously been investigated in a variety of nephrological and urological conditions such as acute kidney injury or prostate cancer.


Differential interactions of muscarinic drugs with binding sites of [3H]pirenzepine and [3H]quinuclidinyl benzilate in rat brain tissue.
Some atypical muscarinic drugs were compared with classical drugs with respect to inhibition of specific binding of [3H]pirenzepine ([3H]PZ) and [3H]quinuclidinyl benzilate ([3H]QNB) to membrane preparations of rat brain. The interactions of the agonists McN-A343 and carbachol with [3H]QNB at muscarinic sites in brain stem preparations were differently modulated in the presence of an excess of PZ. Moreover, McN-A343 exhibited a preferential affinity for [3H]PZ sites in whole brain membranes whereas carbachol bound with high affinity to [3H]QNB sites in brain stem preparations. Various muscarinic agonists and antagonists displayed different affinity patterns in the [3H]PZ and [3H]QNB binding. These data are indicative of two populations of pharmacologically distinguishable binding sites and support the concept of muscarinic receptor heterogeneity in rat brain.


Relationship between a single measurement at baseline of body mass index, glycated hemoglobin, and the risk of mortality and cardiovascular morbidity in type 2 diabetes mellitus.
This study aims to evaluate the relationship between a single measurement at baseline of body mass index (BMI), glycated hemoglobin (HbA1c) and subsequent clinical outcomes in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM were recruited from an outpatient diabetes clinic in a single large teaching hospital in Kingston upon Hull, UK. At baseline, demographics and HbA1c were recorded. Patients were categorized by BMI: normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (>30 kg/m2). Multivariable Cox regression models that included demographic, risk factors, and comorbidities were separately constructed for all-cause, cardiovascular, cancer and sepsis-related mortality, using four groups of HbA1c (<6%, 6.0-6.9%, 7.0-7.9%, and >8%). In total, 6220 patients with T2DM (median age 62 years, 54% male) were followed for a median of 10.6 years. HbA1c levels >8.0% were associated with increased risk of all-cause mortality and cardiovascular death. However, this increased risk was not consistent across the weight categories and reached statistical significance only in overweight patients (BMI 25-29.9 kg/m2). In a large cohort of patients with T2DM elevated HbA1c levels at baseline did not consistently predict increased risk of all-cause and cardiovascular mortality across the different BMI categories.


APP transgenic mice for modelling behavioural and psychological symptoms of dementia (BPSD).
The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioural and psychological symptoms of Alzheimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine.


Shipwreck rates reveal Caribbean tropical cyclone response to past radiative forcing.
Assessing the impact of future climate change on North Atlantic tropical cyclone (TC) activity is of crucial societal importance, but the limited quantity and quality of observational records interferes with the skill of future TC projections. In particular, North Atlantic TC response to radiative forcing is poorly understood and creates the dominant source of uncertainty for twenty-first-century projections. Here, we study TC variability in the Caribbean during the Maunder Minimum (MM; 1645-1715 CE), a period defined by the most severe reduction in solar irradiance in documented history (1610-present). For this purpose, we combine a documentary time series of Spanish shipwrecks in the Caribbean (1495-1825 CE) with a tree-growth suppression chronology from the Florida Keys (1707-2009 CE). We find a 75% reduction in decadal-scale Caribbean TC activity during the MM, which suggests modulation of the influence of reduced solar irradiance by the cumulative effect of cool North Atlantic sea surface temperatures, El Niño-like conditions, and a negative phase of the North Atlantic Oscillation. Our results emphasize the need to enhance our understanding of the response of these oceanic and atmospheric circulation patterns to radiative forcing and climate change to improve the skill of future TC projections.


Highly regioselective synthesis of 2,4,5-(hetero)aryl substituted oxazoles by intermolecular [3+2]-cycloaddition of unsymmetrical internal alkynes.
A robust N-nucleophilic 1,3-N,O-dipole equivalent reacts with unsymmetrical internal alkynes under gold catalysis. Conjugation from a remote nitrogen lone pair enables and controls this convergent and highly regioselective process.


Head and neck manifestations of sarcoidosis.
The records of 42 consecutive patients with biopsy-proven head and neck sarcoidosis were reviewed. A female preponderance of 7.4 to 1 was found. The average age at onset for women was higher than that for men (42 vs. 24 years). The presenting signs and symptoms were noted, and correlations between these and the incidence of abnormal chest radiograph and laboratory findings were examined. Pulmonary involvement was most common in patients with periorbital manifestations or cervical lymphadenopathy. The evaluation of patients with suspected sarcoidosis should include history and physical examination, chest radiograph, PPD and skin tests to rule out anergy, serum chemistry profile, erythrocyte sedimentation rate, and angiotensin converting enzyme level. The diagnosis is confirmed by appropriate histologic examination. Corticosteroid treatment is indicated for patients with uveitis, restrictive pulmonary disease, or other serious systemic manifestations.


Dental students' academic performance before and after the Covid-19 pandemic: A retrospective analysis.
Delivering quality education to students with fair assessment strategies is a key indicator of an excellent educational institution. The present study explored the impact of the COVID-19 pandemic on the academic performance of dental students in terms of the evaluations/grades awarded to them before and during the pandemic. The targeted groups were dental students, studying in the third year of 2018-2019 and 2020-2021 academic years. The sample size included all male and female students who enrolled and completed the following courses: pre-clinical fixed prosthodontics (SDS333), pre-clinical removal prosthodontics (SDS323), clinical operative dentistry-1 (RDS313), and pre-clinical endodontics (RDS323). Evaluations for students who did not complete the requirements were not included in the statistical analysis. Paired sample statistics were used for comparisons between the different groups at p < 0.05. Results revealed statistically significant differences (p ≤ 0.05) for all the course pairs. It was found that students' grades for all the courses during the pandemic year were higher compared to the grades before the pandemic. While female students demonstrated the highest mean difference (6.13) before and during the pandemic year for RDS323, males demonstrated the highest mean difference (8.14) for SDS323. However, both male and female students demonstrated the lowest mean difference (0.25 and 2.03, respectively) for SDS333. The grades were higher during the COVID-19 pandemic. Overall, female students achieved higher grades than male students.


4D printing of products based on soy protein isolate via microwave heating for flavor development.
The aim of this study is to establish food 4D printing products with the property of automatic flavor change by the post-printing application of microwave as an external thermal stimulus. The combination of a formulation comprised of soybean protein isolate (SPI), k-carrageenan (CAR) and vanilla flavor (VNL) was used as printing material. The change in flavor profile was observed by the level of external heat stimulus as a 4D effect. The results of e-nose revealed a significant difference (P < 0.05) in sensors 2, 5, 6, 9, 10, 12 and 13 in the sample added with vanilla flavor meanwhile GC-MS detected 25 volatiles compounds. Notably, four new generated flavor compounds (1-Octen-3-ol, Maltol, Ethyl maltol and eugenal) were identified when added with vanilla flavor. Moreover, e-tongue results indicated the taste characteristics of the sample with vanilla flavor presenting more intense bitterness, astringency, umami, richness and saltiness. The rheological property and water distribution (LF-NMR) determined at different concentrations levels of carrageenan showed that SPI gel made with 3% (w/v) carrageenan was the most suitable for 3D printing among all three concentrations considered in this study. Overall, the results can conclude that the addition of carrageenan and post-printing microwave heating at an optimum level of microwave power enhanced the printability and flavor of SPI gel.


Use of transaortic, transapical, and transcarotid transcatheter aortic valve replacement in inoperable patients.
Transcatheter aortic valve replacement (TAVR) is an effective treatment in patients with severe aortic stenosis unsuitable for surgical aortic valve replacement (SAVR). This study evaluated the early experience with the posttrial application of TAVR, with specific focus on non-transfemoral (TF) access. All patients who underwent posttrial TAVR at Emory University from November 2011 to April 2012 were reviewed. During this time, 44 posttrial TAVRs were performed: TF in 18, transapical in 11, transaortic in 12, and transcarotid in 3. A total of 40.9% of all patients were candidates for TF implantation. Mean age was 78.2 ± 11.3 years, and 34.1% were women. Mean ejection fraction was 0.463 ± 0.164, and 90.2% had New York Heart Association class III to IV heart failure. Fifty percent were diabetic, 27.3% had moderate to severe chronic obstructive pulmonary disease, and 20.5% had a prior stroke. The mean creatinine was 1.63 ± 1.74 mg/dL, 9.1% required preoperative dialysis, and 61.4% had undergone prior cardiac operations. No patients had postoperative myocardial infarction, stroke, or required new dialysis. Intraoperative vascular complications occurred in 11.4%. No patient had more than mild perivalvular leak by transthoracic echocardiography at discharge. Mean postoperative ventilator time was 17.8 ± 40.1 hours. Intensive care unit length of stay was 58.0 ± 67.0 hours. Postoperative hospital length of stay was 6.1 ± 4.7 days. The 30-day mortality was 6.8% (3 of 44) for all patients, despite a mean The Society of Thoracic Surgeons Predicted Risk of Mortality score of 12.6. Less than half of patients deemed appropriate for posttrial TAVR were candidates for TF implantation. The use of all available access routes leads to excellent outcomes in patients deemed inoperable.


Pulmonary thromboembolism associated with gynecologic surgery and pregnancy.
Pulmonary thromboembolism continues to be an infrequent but serious complication of gynecologic surgery and pregnancy. The record of each patient with such a complication treated in two community hospitals during the 10 year period to 1976 was examined in detail. An attempt was made to identify weaknesses in past management and suggest changes to improve future care. Embolism will continue to occur unexpectedly and be of such magnitude as to cause death before effective treatment. can be instituted. Patients at risk can often be identified and prophylactic anticoagulants and antibiotics are appropriate in selected cases. An understanding of the pathology of embolism of and principles of genital sepsis combined with vigorous treatment will save some patients who now would die. If the risks are appreciated, anticoagulants may be used in pregnant patients who are closely monitored. These patients must be alerted to the dangers of both embolism and the treatment.


Systemic signals contribute to induced morphological changes in the hypothalmo-neurohypophysial system.
A systemic injection of hypertonic saline causes morphological changes in the supraoptic nucleus (SON) of the hypothalamus and the posterior pituitary, including withdrawal of astrocytic glial processes from among magnocellular neuroendocrine cells (MNCs) in the SON and increases in neural apposition with the basal lamina (BL) in the posterior pituitary. This study investigated whether systemic adrenalin provides a signal for these changes. Three groups of rats were given intraperitoneal injections of hypertonic (1.5 M) or normal (0.15 M) NaCl and were sacrificed 5 h after injection. One group was given no additional treatment, one group was anesthetized from prior to injection through perfusion, and one group was bilaterally adrenal-medullectomized several days prior to injections. Morphometric analysis of electron micrographs revealed rats given 1.5 M NaCl with no additional treatment showed expected changes in the SON and pituitary. Rats given 1.5 M NaCl and anesthetized showed diminished responses in the SON, and no changes in the pituitary compared to anesthetized rats given 0.15 M NaCl. No changes in withdrawal of glial processes from among MNCs or in neural apposition with the BL were seen in medullectomized animals. Thus, both anesthesia and adrenal-medullectomy interfere with signals for glial retraction and suggest that these responses are mediated by adrenalin.


Association between hypertensive urgencies and subsequent cardiovascular events in patients with hypertension.
To determine whether patients with hypertensive urgency have a higher risk for subsequent cardiovascular events compared with hypertensive patients without this event. Overall, 384 patients with hypertensive urgency and 295 control patients were followed up for at least 2 years. Hypertensive urgency was defined as a systolic blood pressure above 220 mmHg and/or a diastolic blood pressure above 120 mmHg without any evidence of acute end-organ damage. The control group consisted of patients admitted to the emergency department with a systolic blood pressure between 135 to 180 mmHg and a diastolic blood pressure between 85-110 mmHg. The number of cardiovascular events defined as acute coronary syndrome, acute stroke, atrial fibrillation, acute left ventricular failure and aortic aneurysm were consecutively analyzed during follow-up. The median follow-up time was 4.2 years (interquartile range 2.9-5.7 years). Twenty-six patients of the urgency group and 23 patients of the control group were lost for follow-up. Overall, 117 (17%) patients had nonfatal clinical cardiovascular events and 13 had (2%) fatal cardiovascular events. The frequency of cardiovascular events was significantly higher in patients with hypertensive urgencies (88 vs. 42; P = 0.005). The Cox regression analysis identified age (P < 0.001) and hypertensive urgencies (P = 0.035) as independent predictors for subsequent cardiovascular events. Hypertensive urgencies are associated with an increased risk for subsequent cardiovascular events in patients with arterial hypertension.


Prognosis after simple incision and drainage for a first-episode acute pilonidal abscess.
During a 3-year period 73 patients were treated consecutively for a first-episode acute pilonidal abscess with simple incision and drainage under local anaesthesia. In all cases the treatment relieved symptoms and all patients returned to work immediately after treatment. Healing per primam occurred in 42 patients (58 per cent; 95 per cent confidence limits: 45-69) within 10 weeks after treatment. These patients had significantly fewer pits and lateral tracts compared with patients who developed excessive granulation tissue after incision and who required definitive surgical treatment later. Nine patients (21 per cent; 95 per cent confidence limits: 10-37) with healing per primam developed recurrence of their pilonidal disease during the prospective follow-up period (median follow-up period was 60 months, range 36-84 months). Actuarial analysis of the data revealed a constant cure rate of 76 per cent (95 per cent confidence limits: 57-95) after 18 months.