The use of pimonidazole to characterise hypoxia in the internal environment of an in vivo tissue engineering chamber.
The distribution of hypoxic cells in an in vivo tissue engineering chamber was investigated up to 28 days post-implantation. Arteriovenous loops were constructed and placed into bi-valved polycarbonate chambers containing 2 x 10(6) rat fibroblasts in basement membrane gel (BM gel). Chambers were inserted subcutaneously in the groin of male rats and harvested at 3 (n = 6), 7 (n = 6), 14 (n = 4) or 28 (n = 4) days. Ninety minutes before harvest, pimonidazole (60 mg/kg) was injected intraperitoneally. Chamber tissue was removed, immersion fixed, paraffin embedded, sectioned and stained immunohistochemically using hypoxyprobe-1 Mab that detects reduced pimonidazole adducts forming in cells, where pO2 < 10 mmHg. At 3 days a fibrin clot/BM gel framework filled the chamber. Seeded fibroblasts had largely died. The majority of 3 day chambers did not demonstrate tissue growth from the AV loop nor was pimonidazole binding present in these chambers. In one chamber in which tissue growth had occurred strong pimonidazole binding was evident within the new tissue. In four out of six 7 day chambers a broader proliferative zone existed extending up to 0.4 mm (approximately) from the AV loop endothelium which demonstrated intense pimonidazole binding. The two remaining 7 day chambers displayed even greater tissue growth (leading edge > 0.7 mm from the AV loop endothelium), but very weak or no pimonidazole binding. At 14 and 28 days the fibrin/BM gel matrix was replaced by mature vascularised connective tissue that did not bind pimonidazole. Employing a tissue engineering chamber, new tissue growth extending up to 0.4 mm from the AV loop endothelium (chambers < or = 7 days) demonstrated intense pimonidazole binding and, therefore, hypoxia. Tissue growth greater than 0.5 mm from the AV loop endothelium (7-28 days chambers) did not exhibit pimonidazole binding due to a significant increase in the number of new blood vessels and was, therefore, adequately oxygenated.


Organ donation: acceptance and refusal among users of the public health system from Brazil.
The present study sought to identify the perception of a given group of users of the Brazilian Public Health System (Sistema Unico de Saúde) regarding organ donation and to implement an educational policy. Structured interviews were conducted with the aim of describing the profile of donor and nondonor subjects, the importance of organ donation, and the knowledge regarding donation and brain death. One hundred subjects were interviewed: 33% of them considered themselves potential donors; 40% were donors; 13% were nondonors; and 14% were ill-informed potential donors. However, only 40% of users have already officially expressed to their families a willingness to donate. Regarding their knowledge about the propitious moment for organ donation, only 64% of them associated the donation act with brain death. Although the present results revealed that users of the Brazilian Public Health System are prone to organ donation, there actually was a high amount of refusals, which may be due to lack of information and knowledge regarding the donation-transplantation process.


C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn's disease: a post-hoc analysis from ACCENT I.
Secondary loss of response to anti-TNF-α therapy is observed in Crohn's disease patients. Serum C-reactive protein (CRP) levels at baseline and after infliximab induction therapy at week 14 were assessed as predictors for maintained response or remission through 54 weeks of treatment in patients with Crohn's disease who responded to induction therapy. ACCENT I was a multicenter, randomised, placebo-controlled study. Patients who received infliximab induction (weeks 0, 2 and 6) and maintenance (5 or 10 mg/kg every 8 weeks beginning at week 14) therapy were considered. Patients in clinical response or remission to induction therapy at week 14 (n = 212 or n = 138 respectively) were analysed. Associations between CRP levels (cut-off points 0.5-3.0 mg/dL), baseline disease variables and maintained clinical response or remission during maintenance therapy were assessed. A significant association was observed between baseline CRP levels and maintained remission. Forty-five percent of patients with baseline CRP ≥ 0.7 mg/dL vs. 22.0% with CRP < 0.7 mg/dL maintained remission (P = 0.012). CRP normalisation during infliximab treatment (decrease from 0.5 mg/dL at baseline to < 0.5 mg/dL at week 14) resulted in higher probability of maintained response (P < 0.001) or remission (P = 0.052). At week 14 low CRP levels were associated with maintained response (56.6% of patients with CRP < 0.5 mg/dL vs. 37.2% with higher CRP, P = 0.005). No optimal predictive CRP cut-off point was observed. High baseline CRP levels increased the likelihood of maintained remission. Normalised CRP levels at week 14 increased the likelihood of maintained response or remission during 1 year of infliximab maintenance therapy ( NCT00207662).


Phenotypic Variation between Monochorionic Diamniotic Twins with Coffin-Siris Syndrome.
The first known documented case of monochorionic-diamniotic twins with Coffin-Siris syndrome is described in this study. This case is notable because of the phenotypic differences between infants despite having identical genomes and causative variants. Also unique to this case is the clinical influence of early diagnosis using precision medicine techniques.


Inhibitory effect of Ligustrum vulgare leaf extract on the development of neuropathic pain in a streptozotocin-induced rat model of diabetes.
Chronic hyperalgesia and allodynia associated with progressive damage of peripheral neurons are the most prevalent complications of diabetes mellitus. Plants belonging to the family of Oleaceae were traditionally used in folk medicine for the management of diabetes. The aim of this study was to investigate whether an aqueous extract from the leaves of Ligustrum vulgare (common privet) could be useful to target neuropathic pain in a rat streptozotocin (STZ) model of diabetes. The chemical composition of the aqueous extract from privet leaf was characterized with the UHPLC-DAD-MS method and the analytical quantification of its constituents was performed with HPLC-DAD. Mechanical hyperalgesia and allodynia were evaluated with the Randall-Selitto and von Frey tests. Our investigation revealed the presence of secoiridoids: oleacein (23.48 ± 0.87 mg/g), oleocanthal (8.44 ± 0.08 mg/g), oleuropein (1.50 ± 0.01 mg/g), as well as phenylpropanoids: echinacoside (6.46 ± 0.07 mg/g), verbascoside (4.03 ± 0.04 mg/g) and p-coumaroyl glucarates in the dried aqueous extract of privet leaves. Behavioral data indicated that chronic intraperitoneal administration of the extract (50-200 mg/kg) for 21 days resulted in a decrease in diabetes-induced hyperalgesia and allodynia. Blood glucose levels remained unaltered, while body weight and water intake decreased significantly. The aqueous privet leaf extract could serve useful in facilitating treatment of painful diabetic neuropathy. Additionally, the study showed that the antihyperalgesic activity of Ligustrum vulgare leaf extract is not likely related to its antihyperglycemic properties.


In vitro evaluation of a measurement method to analyze the interdental, mesially directed force.
In order to evaluate interdental forces as a benchmark for mesial drift, a measurement technique was tested and evaluated on a human specimen. The measurement technique is based on the principle that a mesially directed horizontal force (FH) within a complete dental arch has an effect on interdental friction at the points of contact. The dynamic force (FZ), needed to pull out a defined metal strip from the interdental space is equal to the interdental frictional force (FR). Assuming unmodified approximal surfaces and unchanged tooth mobility in a complete dental arch, relative modifications of the interdental frictional force level provide a way of measuring horizontal force fluctuations. The validity of this measurement technique was measured by applying mesially directed forces of 1 to 5 N to the distal surface of the 2nd molar in a human specimen. The frictional forces measured increased in proportion to the distally applied force. The mesially directed force on the 2nd molar was transmitted in the dental arch anteriorly up to the incisor region and resulted in an increase of frictional forces. The reproducibility of this measurement technique was tested by quantitative analysis of potential measurement errors in the human specimen. The effect on interdental force measurement of the speed at which the metal strip is pulled was evaluated in a range of 50 to 500 mm/min. At the maximum pulling speed of 500 mm/min, a maximum scatter of 8% was recorded. Dependency of the dynamic force on direction of pull was measurable only when the metal strip was angled at more than 15 degrees. Experimental tests on the human specimen confirmed that the measurement technique presented here is sufficiently valid and reproducible for clinical long-term studies of interdental forces.


Cyclosporine A-loaded colon-targeted oral nanomicelles self-assembly by galactosylated carboxymethyl chitosan for efficient ulcerative colitis therapy.
An oral galactosylated carboxymethyl chitosan polymeric nanomicelles (Gal-N-CMCS NPs) embedded in chitosan-alginate hydrogel (CA-Gel) was developed to load cyclosporine A (CyA) as therapeutic agents against ulcerative colitis (UC). Galactose modified CMCS with macrophage targeting characteristic and CyA via a simple ultrasonication method to form Gal-N-CMCS/CyA NPs, and mixed CA-Gel to acquire the final formulation (Gal-N-CMCS/CyA Gel). The generated Gal-N-CMCS/CyA NPs displayed a desirable particle size (206.8 nm), negative surface charge (-19.5 mV), and high encapsulating efficiency (89.6 %). The morphology and release profiles were also charactered by transmission electron microscope [1] and dialysis method, respectively. Strikingly, the mucus penetration of Gal-N-CMCS/CyA NPs exceeded 90 % within 90 min. The Gal-N-CMCS NPs internalized by macrophages were 3.3-fold higher than CMCS-N NPs, thereby, enhancing the anti-inflammatory activities of NPs. Meanwhile, these NPs exhibited excellent biocompatibility, reduced the toxic effect of CyA, and targeting ability on inflammatory macrophages both in vitro and in vivo. Most importantly, in vivo studies revealed that CyA NPs could efficiently target the inflamed colon, remarkably alleviate inflammation, repair mucosal and reconstructed colonic epithelial barriers in UC mice induced by dextran sulfate sodium (DSS) via Toll-like receptor 4 -Nuclear factor kappa-B (TLR4-NF-κB) pathway. Our findings suggest that these high-performance and facilely fabricated Gal-N-CMCS/CyA NPs could be developed as a promising drug carrier for oral UC treatment.


Remote gestational weight gain monitoring in a large low-risk US population.
Over the past decade there have been rapid advancements in telemedicine and mobile health technology (mHealth) and rapid increases in adoption of these technologies among OB-GYN providers. Mobile technology is routinely used in the general adult population to simplify monitoring of food intake and weight. Studies have demonstrated that weight loss achieved via remote monitoring, through use of wi-fi scales and web applications, is similar to weight loss achieved with in-person support. These technologies also increase flexibility for subjects and providers. However, there has been limited large-scale research to evaluate the use of these technologies to improve adherence to weight-gain recommendations during pregnancy. To evaluate gestational weight gain tracking in a large low-risk obstetrical population using remote patient monitoring and a mobile phone app. Self-reported age, height, estimated due date, and weight data were extracted from low-risk, singleton pregnancies entered from 50,769 participants who were enrolled in the BabyScripts TM phone app between 1 January 2016 and 1 March 2020. After data cleaning, 15,468 participants were included the final analysis. Linear regression and Spearman's correlation were used to examine the relationships between total weight gain, rate of weight gain, body mass index (BMI), postpartum weight loss, and app engagement. The average weight gain in the first, second, and third trimester were 0.09 ± 1.8 kg, 4.2 ± 3.3 kg, and 3.9 ± 3.9 kg, respectively. The average rate of weight gain per week for the second and third trimesters were 0.5 ± 0.4 kg/wk and 0.6 ± 0.8 kg/wk, respectively. Participants with higher initial BMI had slower rate of weight gain than those with lower initial BMI (r = -0.24, r = -0.05, for second and third trimester, respectively). Overall, 21.4% of participants met the Institutes of Medicine (IOM) recommendation for total weight gain during pregnancy. Patients who were highly engaged with the mobile app had increased adherence to the IOM guidelines (29.8% vs. 9.4%, p < 0.001). A larger proportion of highly engaged patients adhered to the IOM guidelines for rate of weight gain in the second and third trimester, compared to the lowest engaged patients (12.7% vs. 6.8%, p < 0.001). On average, participants lost 8.8 ± 3.3 kg over an average of 8.1 ± 4.6 weeks in the immediate postpartum period. This weight loss was positively associated with engagement (r = 0.3, p < 0.001). Engagement with the mobile app was associated with increased adherence to the IOM gestational weight gain guidelines and with increased postpartum weight loss. Use of remote patient monitoring in conjunction with mHealth technology may be a strategy to improve adherence to IOM guidelines.


Pulmonary cryptococcosis in rheumatoid arthritis (RA) patients: comparison of imaging characteristics among RA, acquired immunodeficiency syndrome, and immunocompetent patients.
The imaging characteristics of cryptococcosis in rheumatoid arthritis (RA) patients were analyzed by comparing them with those of acquired immunodeficiency syndrome (AIDS) and immunocompetent patients, and the imaging findings were correlated with pathological findings. Two radiologists retrospectively compared the computed tomographic (CT) findings of 35 episodes of pulmonary cryptococcosis in 31 patients with 3 kinds of underlying states (10 RA, 12 AIDS, 13 immunocompetent), focusing on the nature, number, and distribution of lesions. The pathological findings of 18 patients (8 RA, 2 AIDS, 8 immunocompetent) were analyzed by two pathologists, and then correlated with imaging findings. The frequencies of consolidation and ground glass attenuation (GGA) were significantly higher, and the frequency of peripheral distribution was significantly lower in the RA group than in the immunocompetent group. Peripheral distribution was less common and generalized distribution was more frequent in the RA group than in the AIDS group. The pathological findings of the AIDS and immunocompetent groups reflected their immune status: There was lack of a granuloma reaction in the AIDS group, and a complete granuloma reaction in the immunocompetent group, while the findings of the RA group varied, including a complete granuloma reaction, a loose granuloma reaction and a hyper-immune reaction. Cases with the last two pathologic findings were symptomatic and showed generalized or central distribution on CT. Cryptococcosis in the RA group showed characteristic radiological and pathological findings compared with the other 2 groups.


The Camino intracranial pressure device in clinical practice: reliability, handling characteristics and complications.
Intracranial pressure monitoring has a key role in the management of patients developing increased intracranial pressure (ICP). We adopted the Camino fiberoptic system for intracranial pressure measurement in 1993 in our neurosurgical department. The aim of this study was to investigate reliability, handling characteristics and complication rate of the Camino intracranial pressure device. In an eighteen month period, we prospectively investigated 118 patients with intracranial pathology undergoing Camino fiberoptic intraparenchymal or intraventricular ICP monitoring. The assessment of reliability of ICP monitoring according to patients clinical condition, to cranial computed tomography (CCT) findings and ICP waveform was carried out. Position of the probe and intracranial bleeding complications related to probe insertion were confirmed by CCT. Technical complications, as well as infections due to the device, were documented. In vivo recalibration was performed in 22 patients. At the end of the measuring period the drift of the probe was evaluated and the accuracy of the fiberoptic device was measured by performing a two point calibration. Recordings of intracranial pressure were carried out with 136 Camino devices (104 parenchymal, 32 ventricular) in 118 patients with an average measuring time of 94.1 +/- 79.1 hrs. One hundred and fifteen Camino intracranial pressure devices (85.2%) demonstrated reliability according to the predetermined clinical parameters. The actual mean drift after removal of the devices was 3.4 mmHg +/- 3.2 with an actual daily drift of 3.2 +/- 17.2 mmHg. Recorded complications included infection (0.7%), intraparenchymal haematoma (5.1%), and a high complication rate (23.5%) with regard to technical aspects. The Camino intracranial pressure system offers reliable ICP measurements in an acceptable percentage of devices, and the advantage of in vivo recalibration. The high incidence of technical complications identifies a need for improvement in the fiberoptic cable and the fixation system.


NPAS4 Facilitates the Autophagic Clearance of Endogenous Tau in Rat Cortical Neurons.
Tau, a microtubule-binding phosphoprotein, plays a critical role in the stabilisation of microtubules and neuronal function. However, hyperphosphorylated tau is involved in the pathogenesis of Alzheimer's disease (AD) and other tauopathies. The facilitation of tau clearance is now regarded as a valid therapeutic strategy for these neurodegenerative tauopathies. Here, we provide the first demonstration that the over-expression of neuronal PAS domain protein 4 (NPAS4)-induced autophagy and effectively facilitated the clearance of endogenous total and phosphorylated tau in rat primary cortical neurons. Moreover, the activation of autophagy by serum depletion significantly decreased endogenous total and phosphorylated tau levels. Autophagy inhibitors, such as 3-methyladenine (3-MA) and chloroquine (CQ), induced tau aggregation. However, NPAS4 over-expression reversed the aggregation of tau that was induced by the inhibition of autophagy. Interestingly, proteasome inhibition by MG132, had no effect on autophagy, but did reduce tau levels, indicating that NPAS4 may also degrade tau proteins through an unknown proteasome-mediated mechanism. Furthermore, NPAS4 did not alter the activity of two major tau kinases, glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5). Taken together, the results indicate that targeting NPAS4 could provide a therapeutic approach for the treatment of AD and other tauopathies.


The analgetic effects of an intrathecally administered partial opiate agonist, nalbuphine hydrochloride.
Nalbuphine (0.1-200 micrograms), unlike morphine (0.1-10 micrograms) administered intrathecally had no effect on the tail flick or hot plate response latencies. In contrast, both intrathecal nalbuphine and morphine inhibited, in a monotonic, dose dependent fashion, the writhing evoked by intraperitoneally administered acetic acid (ED50 = 38 nmol and 1.12 nmol, respectively.) The effects of intrathecal nalbuphine and morphine was antagonized by an equal dose of naloxone administered systemically. Co-intrathecal administration of morphine and nalbuphine revealed that a maximum inhibition of writhing could be obtained with low doses of either drug, while the effects of higher doses of either drug were attenuated as compared to the effects produced by the high dose of either drug alone. These data are consistent with the suggestion that nalbuphine exerts its agonistic effect through a mechanism that is pharmacologically distinct from that of morphine, and the likelihood of two populations of opioid receptors associated with the pain response evoked by thermal and visceral afferents, respectively is considered.


Profiling helicopter emergency medical service winch operations involving physicians in Queensland, Australia.
To analyse the mission profiles of helicopter emergency medical service (HEMS) winch operations involving LifeFlight Retrieval Medicine physicians in Queensland, Australia, specifically focusing on patients' clinical characteristics, extrication methods and scene times. A retrospective analysis was performed to identify all helicopter winch missions involving physicians during 2019. Demographic, clinical and non-clinical data were accessed from an electronic database used to log cases and findings presented using descriptive statistics. Out of 4356 HEMS missions involving physicians, 100 (2.3%) were winch operations. Of these, 31 (31%) occurred overwater and 12 (12%) at night. In total, 106 patients were attended, and eight patient deaths occurred. Most patients were traumatically injured (66%), male (66%) and had a median (interquartile range) age of 43.5 (28-59) years. Thirteen missions (13%) involved drowning victims. This group had a higher burden of injury and comprised half of the patients treated with endotracheal intubation. Median scene time was 30 min (20-40), and the winch stretcher was the predominant patient extrication method. Physician winching occurred in 63 (63%) missions and was associated with increased scene time and increased use of the winch stretcher. Winch operations involving physicians occur infrequently in Queensland HEMS, although almost a third of missions occur overwater. Drowning victims are encountered more frequently than reported elsewhere in Australian HEMS and comprised half of the patients who underwent endotracheal intubation. Patients' severity of illness and injury may contribute to the associations between winching of physicians, increased scene times and increased use of the winch stretcher.


The Diagnostic Role of Shear Wave Elastography and Superb Microvascular Imaging in the Evaluation of Suspicious Microcalcifications.
The aim of this study was to investigate the role of superb microvascular imaging (SMI) and shear wave elastography (SWE) in the prediction of malignancy and invasiveness of isolated microcalcifications (MC) that can be visualized by ultrasonography (US). Sixty-seven women with MC, who were considered suspicious on mammography were evaluated. Only those lesions that could be visualized by US and presented as non-mass lesion were included. They were evaluated by B-mode US, SMI, and SWE before US-guided core-needle biopsy. B-mode US, SMI (vascular index (SMIvi)), and SWE (E-mean, E-ratio) findings were compared with histopathologic features. Pathology confirmed 45 malignant (21 invasive and 24 in situ carcinomas) and 22 benign lesions. There was a statistically significant difference between malignant and benign groups in terms of size (P = .015), distortion (P = .028), cystic component (P < .001), E-mean (P < .001), E-ratio (P < .001), and SMIvi (P = .006). For differentiation of invasiveness E-mean (P = .002), E-ratio (P = .002), and SMIvi (P = .030) were statistically significant. According to ROC analysis E-mean (cut-off point at 38 kPa) was the most sensitive (78%) and the most specific (95%) value among four numeric parameters (size, SMI, E-mean, and E-ratio) with AUC = 0.895, PPV = 97%, and NPV = 68% in detecting malignancy. In the evaluation of invasiveness, the most sensitive (71.4%) method was SMI (cut-off point at 3.4) and the most specific (72%) method was E-mean (cut-off point at 91.5 kPa). Our study shows that adding SWE and SMI to the sonographic evaluation of MC would be an advantage for US-guided biopsy. Including suspicious areas according to SMI and SWE in the sampling area can help target the invasive part of the lesion and avoid underestimation of core biopsy.


[Evolution of the access to the kidney transplantation in France of foreign patients and French patients living in overseas territories].
In France, foreign patients, whether resident or not in France, can register on the national waiting list under administrative and financial conditions. We performed a retrospective analysis to evaluate the access to kidney transplantation on a cohort 2004-2008, using the national registry. Among the 14,732 patients registered during this period, 15.3% are of non-French nationality (3.4% other European, 5.9% North African, 3.9% sub-Saharan African, 2.9% other). Among the 84.6% of French nationality, 3.3% are living in French overseas territories. Compared to the 17.6-month median waiting time of the cohort, median waiting time differs significantly between groups, from 15.7 months for mainland French patients to 36 months for sub-Saharan African patients. Despite the regular development of the allocation rules, these disparities in access to transplantation are mainly, but not completely, explained by blood group or HLA matching difficulties. After adjustment for the other factors known to be significantly linked to a difficult access to transplantation, North and sub-Saharan African patients have the worst difficulties. Future research should consider nonmedical factors, such as socio-economic or socio-cultural factors, potentially relevant to avoid disparities in access to transplantation and should aim at developing specific interventions.


Over expression of IL-10 by macrophages overcomes resistance to murine filariasis.
Individuals infected with parasitic helminths are able to tolerate the presence of parasites for considerable time without clinical pathology. Immunosuppressive responses induced by the filarial parasite are considered responsible for this long-lasting relationship, inuring to the benefit of both parasite and host. In order to directly link IL-10 with parasite survival, we infected mice, in which over expression of IL-10 was restricted to macrophages under control of the CD68 promoter (macIL-10tg), with Litomosoides sigmodontis. IL-10 overexpression by macrophages led to increased susceptibility with a significantly higher number of adult worms. Most profound, IL-10 overexpression was sufficient to convert resistant FVB wild-type mice towards a patent phenotype, since microfilariae were exclusively found in macIL-10tg mice. These findings were associated with reduced Th2 cytokine production in macIL-10tg mice. Expression of arginase-1, Ym1 and Fizz1, genes that are found strongly expressed in murine alternatively activated macrophages, were detected in macIL-10tg mice. Thus, IL-10 produced by macrophages with characteristics of alternative activation can overcome resistance and allow full patency in murine filariasis.


Detecting contradictions from IoT protocol specification documents based on neural generated knowledge graph.
Due to the boom of Internet of Things (IoT) in recent years, various IoT devices are connected to the Internet and communicate with each other through network protocols such as the Constrained Application Protocol (CoAP). These protocols are typically defined and described in specification documents, such as Request for Comments (RFC), which are written in natural or semi-formal languages. Since developers largely follow the specification documents when implementing web protocols, they have become the de facto protocol specifications. Therefore, it must be ensured that the descriptions in them are consistent to avoid technological issues, incompatibility, security risks, or even legal concerns. In this work, we propose Neural RFC Knowledge Graph (NRFCKG), a neural network-generated knowledge graph based contradictions detection tool for IoT protocol specification documents. Our approach can automatically parse the specification documents and construct knowledge graphs from them through entity extraction, relation extraction, and rule extraction with large language models. It then conducts an intra-entity and inter-entity contradiction detection over the generated knowledge graph. We implement NRFCKG and apply it to the most extensively used messaging protocols in IoT, including the main RFC (RFC7252) of CoAP, the specification document of MQTT, and the specification document of AMQP. Our evaluation shows that NRFCKG generalizes well to other specification documents and it manages to detect contradictions from these IoT protocol specification documents.


Increased expression of CD25 and HLA-DR on lymphocytes recruited into the peritoneal cavity in non-infected CAPD patients.
The impact of uremia per se, peritoneal dialysis (PD) and hemodialysis (HD) treatment was evaluated on characteristics of lymphocytes. CD4, CD8, CD25 and HLA-DR were analyzed, with flow cytometry, in lymphocytes prepared from peripheral blood of uremic (n = 10) and hemodialysis patients (n = 10). Peritoneal dialysate was also obtained from patients on CAPD (n = 12). A decreased relative and absolute lymphocyte count was observed in peripheral blood from uremic, HD and CAPD patients compared to healthy controls (p < 0.03, p < 0.03 and p < 0.02, respectively). On the other hand, the relative distribution of lymphocytes was significantly higher in peritoneal dialysate compared to peripheral blood of CAPD patients (p < 0.02). Likewise, the absolute CD4 positive lymphocyte count was lower in the peripheral blood from uremic. HD and CAPD patients as compared to healthy controls (p < 0.001, respectively). In CAPD patients the relative distribution of CD4 positive cells (p < 0.001) was lower, while quantitative CD25 level (p < 0.01) and the relative count of HLA-DR (p < 0.0001) was increased in the peritoneal dialysate compared to blood. Taken together a selective activation of lymphocytes in peritoneal dialysate as compared to peripheral blood from uremic, HD and CAPD patients was observed. The altered biological function of the inflammatory cells may therefore explain the increased susceptibility to infectious diseases.


Laboratory characteristics of pregnant compared to non-pregnant women infected with SARS-CoV-2.
Laboratory characteristics of SARS-CoV-2 infection did not differ between pregnant and non-pregnant women. A trend of lower lymphocyte count was observed in the pregnant women group PURPOSE: Laboratory abnormalities, which characterize SARS-CoV-2 infection have been identified, nevertheless, data concerning laboratory characteristics of pregnant women with SARS-CoV-2 are limited. The aim of this study is to evaluate the laboratory characteristics of pregnant compared to non-pregnant women with SARS-CoV-2 infection. A retrospective cohort study of all pregnant women with SARS-CoV-2 who were examined at the obstetric emergency room in a tertiary medical center between March and April 2020. Patients were compared with non-pregnant women with SARS-CoV-2 matched by age, who were examined at the general emergency room during the study period. All patients were confirmed for SARS-CoV-2 on admission. Clinical characteristics and laboratory results were compared between the groups. Study group included 11 pregnant women with SARS-CoV-2, who were compared to 25 non-pregnant controls. Respiratory complaints were the most frequent reason for emergency room visit, and were reported in 54.5% and 80.0% of the pregnant and control groups, respectively (p = 0.12). White blood cells, hemoglobin, platelets, and liver enzymes counts were within the normal range in both groups. Lyphocytopenia was observed in 45.5% and 32% of the pregnant and control groups, respectively (p = 0.44). The relative lymphocyte count to WBC was significantly reduced in the pregnant group compared to the controls [13.6% (4.5-19.3) vs. 26.5% (15.7-29.9); p = 0.003]. C-reactive protein [20(5-41) vs. 14 (2-52) mg/dL; p = 0.81] levels were elevated in both groups but without significant difference between them. Laboratory characteristics of SARS-CoV-2 infection did not differ between pregnant and non-pregnant women, although a trend of lower lymphocyte count was observed in the pregnant women group.


Involvement of the nitric oxide-cyclic GMP pathway in the desensitization of bradykinin responses of cultured rat sensory neurons.
Bradykinin (BK) excites a subset of dorsal root ganglion neurons by inducing an inward cation current (IBK) that strongly desensitizes and is accompanied by elevations in cGMP. We have examined the links between cGMP metabolism and IBK. The BK dose dependencies of IBK activation, desensitization, and cGMP production are comparable. Stimulation (with sodium nitroprusside [NP] or 8-bromo-cGMP [8Br-cGMP]) or inhibition (with methylene blue, hemoglobin, and nitric oxide synthase [NOS] inhibitors) of cGMP levels did not mimic or diminish IBK. However, desensitization was affected by the following agents: first, desensitization was enhanced by NP and reduced by NOS inhibitors. Second, the effects of NOS inhibitors could be overcome by 8Br-cGMP or L-arginine. Third, 8Br-cGMP modification of desensitization required receptor occupancy. We conclude that the NO-cGMP pathway affects a component of IBK desensitization at the receptor or G protein level.


[Times of gender equity: a description of the inequalities between autonomous communities, Spain 2006-2014].
Gender equity (GE) is a structural determinant of health inequalities. In this light, our objective is to show the evolution of gender equity in the Spanish autonomous communities since 2006, prior to the enactment of the Equality Act (2007) and the economic crisis (2008), until 2014. Ecological study of gender equity in the 17 Spanish autonomous communities from 2006-2011-2014. We have calculated: 1) modified gender equity index (MGEI) for the autonomous communities (0=equity, ±1=inequity); 2) interregional and temporal convergences in gender equity. The MGEI in the autonomous communities in 2014 has negative values close to 0 (inequity towards women). There is no interregional convergence due to the dispersion increase (2006: 0.1503; 2011: 0.2280; 2014: 0.4964), and no temporal convergence due to the lack of progress of the autonomous communities with poor gender equity. The gender gap in economic activity continues to be unfavourable to women, decreasing in all communities between 2006 and 2011 but increasing in six communities in 2014. The gender gap in education from 2006-2011-2014 has positive values close to 0 (unfavourable to men), while the gender gap in empowerment is unfavourable to women, representing the most significant gender equity disparity. Inter-community dispersion of economic activity and education did not change between 2006 and 2014, while inter-community dispersion of empowerment increased. The level of gender equity achieved in the Spanish autonomous communities in 2006 was lost during the economic crisis, as gender equity disparities between the communities had increased by 2014. Gender inequity continues to be unfavourable to women.


Quality of life, depression, and anxiety in patients with a subcutaneous versus transvenous defibrillator system.
Use of the subcutaneous implantable defibrillator (S-ICD) has increased because the device received US Food and Drug Administration approval in 2012, but we still know little about whether the quality of life (QoL) of patients with an S-ICD versus a transvenous ICD (TV-ICD) is comparable. We compared S-ICD patients with TV-ICD patients on QoL, depression, and anxiety up to 12 months' follow-up. A matched cohort of S-ICD (N = 167) and TV-ICD patients (N = 167) completed measures on QoL, depression, anxiety, and personality at baseline, 3, 6, and 12 months post implant. Data were analyzed using multivariable modeling with repeated measures. In adjusted analyses, we found no statistically significant differences between cohorts on physical and mental QoL and depression (all Ps > .05), while S-ICD patients reported lower anxiety than TV-ICD patients (P = 0.0007). Both cohorts experienced improvements in physical and mental QoL and symptoms of depression and anxiety over time (all Ps < .001), primarily between implant and 3 months. These improvements were similar for both cohorts with respect to physical and mental QoL and anxiety (Ps > .05), while S-ICD patients experienced greater reductions in depressive symptoms (P = .0317). The QoL and depression levels were similar in patients with an S-ICD and a TV-ICD up to 12 months' follow-up, while S-ICD patients reported lower anxiety levels and a greater reduction in depression over time as compared to TV-ICD patients. This knowledge may be important for patients and clinicians, if the indication for implantation allows both the S-ICD and the TV-ICD, making a choice possible.


The effects of ziprasidone, clozapine and haloperidol on lipid peroxidation in human plasma (in vitro): comparison.
Oxidative injury in schizophrenia can be caused by the disease itself and probably by antipsychotics treatment. The aim of the study was to establish whether there is a difference between ziprasidone, clozapine and haloperidol effect on lipid peroxidation in human plasma, measured by the level of thiobarbituric acid reactive substances (TBARS). The samples of plasma from healthy subjects were incubated with the drugs (1 and 24 h) and compared with control samples. The levels of TBARS were measured spectrophotometrically, according to the Rice-Evans method. The multifactorial variance analysis ANOVA II test showed that the differences in TBARS levels significantly depended on the studied drugs (ziprasidone 40 ng/ml, haloperidol 4 ng/ml and clozapine 350 ng/ml) (F = 3.248 p = 0.047) and (ziprasidone 139 ng/ml, haloperidol 20 ng/ml and clozapine 420 ng/ml) (F = 2.248, p = 2.9 × 10(-5)). Statistically increased levels of TBARS after 24 h incubation of plasma with ziprasidone 139 ng/ml and haloperidol 20 ng/ml (p < 0.001, p < 0.05 respectively) in comparison with control samples were observed. Clozapine did not significantly (p > 0.05) increase TBARS level in plasma in comparison with control samples. The results obtained in the study showed that ziprasidone and haloperidol contrary to clozapine induced a significant increase in plasma lipid peroxidation.


Neutrophil collagenase, gelatinase, and myeloperoxidase in tears of patients with stevens-johnson syndrome and ocular cicatricial pemphigoid.
To investigate the levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in tears of patients with Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP). Prospective, noninterventional cohort study. Four SJS patients (7 eyes), 19 OCP patients (37 eyes), and 20 healthy controls who underwent phacoemulsification (40 eyes). Tear washes were collected from all patients and were analyzed for levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 using multianalyte bead-based enzyme-linked immunosorbent assays. Total MMP activity was determined using a fluorometric assay. Correlation studies were performed between the various analytes within study groups. Levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 (in nanograms per microgram of protein) and total MMP activity (in relative fluorescent units per minute per microgram of protein) in tears; MMP-8-to-TIMP-1 ratio; MMP-9-to-TIMP-1 ratio; and the correlations between MMP-8 and MMP-9 and both MMP and MPO. MMP-8, MMP-9, and MPO levels were elevated significantly in SJS and OCP tears (SJS>OCP) when compared with controls. The MMP activity was highest in SJS patients, whereas OCP patients and controls showed lower and similar activities. The TIMP-1 levels were decreased in SJS and OCP patients when compared with those in controls, with levels in OCP patients reaching significance. The MMP-8-to-TIMP-1 and MMP-9-to-TIMP-1 ratios were markedly elevated in SJS and OCP tears (SJS>OCP) when compared with those of controls. Across all study groups, MMP-9 levels correlated strongly with MMP-8 and MPO levels, and MMP-8 correlated with MPO, but it did not reach significance in SJS patients. There was no relationship between MMP-7 and MPO. Because MMP-8 and MPO are produced by inflammatory cells, particularly neutrophils, the correlation data indicate that they may be the common source of elevated enzymes, including MMP-9, in SJS and OCP tears. Elevated MMP-to-TIMP ratios and MMP activity suggest an imbalance in tear MMP regulation that may explain the predisposition of these patients to demonstrate corneal melting and chronic complications associated with persistent inflammation. Myeloperoxidase in tears may be a sensitive and specific marker for the quantification of ocular inflammation.


[Coronary aneurysm in Behcet's disease. Report of a case].
Cardiac involvement is rare in Behçet's disease. The authors report the case of a young patient with Behçet's disease and multiple cardiac complications. The remarkable feature of this case was the presence of a coronary artery (first diagonal) aneurysm associated with multiple venous thromboses. Anticoagulant therapy was changed for a platelet aggregant. Surgery was not indicated because of the fragility of the vessels.


Diagnosis of Pompe's disease using leukocyte preparations. Kinetic and immunological studies of 1,4-alpha-glucosidase in human fetal and adult tissues and cultured cells.
Kinetic and immunological studies of 1,4-alpha-glucosidase show that the distribution of acid, renal and neutral alpha-glucosidase at pH 4.0 and 6.5 is as follows: in liver and cultured fibroblasts and amniotic fluid cells the activity at pH 4.0 is mainly due to the acid enzyme. Even at pH 6.5, the activity is largely due to the residual activity of the acid enzyme. In kidney and leukocytes, however, the activity by acid enzyme at pH 4.0 represents only 30-60% of the total activity and the remaining activity is from renal enzyme. At pH 6.5, the activity is almost exclusively of renal enzyme. Renal alpha-glucosidase has a higher affinity for maltose (Km, 0.8 mmol/l) than acid enzyme, however; for glycogen acid enzyme shows the highest affinity (20.7 g/l). There is no significant difference in the kinetic characteristics of alpha-glucosidase between fetal and adult tissues. In kidney, however, a relative increase in renal enzyme to acid enzyme with age is found, i.e. in fetal kidney the alpha-glucosidase activity at pH 4.0 is more than twice that at pH 6.5, whereas in adult kidney, the activity ratio at pH 4.0-6.5 is approximately 1. Antibodies for human liver acid alpha-glucosidase decrease the alpha-glucosidase activity in normal leukocytes by 22-75% at pH 4.0 (0.54-3.8 nmol/min per mg protein). The decrease is significantly lower in patients with Pompe's disease (0-0.11 nmol/min per mg protein) as well as in their parents and some siblings (0.15-0.70).


Meta-Analysis Comparing Primary Percutaneous Coronary Intervention Versus Pharmacoinvasive Therapy in Transfer Patients with ST-Elevation Myocardial Infarction.
ST-elevation myocardial infarction patients presenting at non-percutaneous coronary intervention (PCI)-capable hospitals often need to be transferred for primary percutaneous coronary intervention (PPCI). This increases time to revascularization, leading to increased risk of in-hospital mortality. With recent focus on total ischemic time rather than door-to-balloon time as the principal determinant of outcomes in ST-elevation myocardial infarction patients, pharmacoinvasive therapy (PIT) has gained attention as a possible improvement over PPCI in patients requiring transfer. Our objective was to observe how PIT stands against PPCI in terms of safety and efficacy. Electronic databases were searched for randomized controlled trials and observational studies comparing PPCI to PIT. PIT was defined as administration of thrombolytic drugs followed by immediate PCI only in case of failed thrombolysis. Results from studies were pooled using a random-effects model. We identified 17 relevant studies (6 randomized controlled trials, 11 observational studies) including 13,037 patients. Overall, there was no significant difference in short-term mortality (odds ratio [OR] = 1.20 [0.97 to 1.49]; I2 = 14.2%; p = 0.099); however, PIT significantly decreased short-term mortality (OR = 1.46 [1.08 to 1.96]; I2 = 0%; p = 0.01) in those studies with a symptom-onset-to-device time ≥200 minutes. There was a significantly lower risk reinfarction (OR = 0.69 [0.49 to 0.97]; I2 = 0%; p = 0.033) in the PPCI group, while the risk of cardiogenic shock was significantly higher (OR = 1.48 [1.13 to 1.94]; I2 = 0%; p = 0.005). In conclusion, PIT versus PPCI decisions should preferably be customized in patients presenting to non-PCI capable hospitals. Factors that need to be considered include symptom-onset to first medical contact time, expected time of transfer to a PCI-capable hospital, and patients risk factors.


[Oxygen-dependent indicators of phagocytosis in an infection caused by Trychophyton rubrum].
A clinico-cytochemical investigation of 27 patients with rubrophytia revealed a suppression of phagocytic activity of neutrophils conjugated with inhibition of the nitroblue tetrazolium test. It was confirmed that inclusion into the therapeutic complex of chlorophyllipt allows to level the intraleucocytic metabolic disbalance, to achieve enhanced regression of clinical manifestations of mycosis.


Cimetidine and ranitidine protect against cold restraint-induced ulceration in rat by suppressing gastric acid secretion.
The effect of the H2-receptor antagonists cimetidine and ranitidine on pentagastrin-stimulated gastric acid secretion in anesthetized rats, and gastric mucosal lesion formation and gastric motility in unanesthetized cold-restrained rats was studied. Both cimetidine and ranitidine suppressed pentagastrin-stimulated gastric secretion in a dose-dependent fashion. Cold restraint-induced lesion formation was not prevented with doses of both agents that inhibited acid secretion by 75%. Doses which suppressed pentagastrin-stimulated acid secretion more than 90% significantly prevented the development of gastric mucosal lesions produced by cold restraint. Doses of both H2 blockers which demonstrated significant suppression of lesion formation had no effect on cold restraint-stimulated gastric contractility. We conclude that cimetidine and ranitidine suppress cold restraint-induced lesion formation by suppressing acid secretion and not by suppressing gastric contractility.


Risk Factors for Sexual Dysfunction Among Women and Men: A Consensus Statement From the Fourth International Consultation on Sexual Medicine 2015.
This article presents a review of previous research concerning risk factors for sexual dysfunction in women and men. The aim is to evaluate past research studies to determine the contribution of all risk factors to the development and maintenance of sexual dysfunction among women and men. Studies were organized under a biopsychosocial framework, with the bulk of studies of women and men having investigated the role of biological factors. The outcome measures were the data on factors for sexual dysfunction. Many more studies investigated risk factors for sexual dysfunction in men than in women. For women and men, diabetes, heart disease, urinary tract disorders, and chronic illness were significant risk factors for sexual dysfunction. Depression and anxiety and the medications used to treat these disorders also were risk factors for sexual dysfunction in women and men. In addition, substance abuse was associated with sexual dysfunction. Many other social and cultural factors were related to sexual dysfunction in women and men. Psychosocial factors are clearly risk factors for sexual dysfunction. Women and men with sexual dysfunction should be offered psychosocial evaluation and treatment, if available, in addition to medical evaluation and treatment. The impact of social and cultural factors on sexual function requires substantially more research. The evidence that erectile dysfunction is a harbinger of other forms of cardiovascular disease is strong enough to recommend that clinical evaluation for occult cardiovascular disease should be undertaken in men who do not have known cardiovascular disease but who develop organic erectile dysfunction, especially in men younger than 70 years.


The computerized dental office of the future.
The computer will soon become an indispensable tool for the private dental practitioner. It will aid in planning, managing, operating and even become part of the delivery of service to patients. The key is in understanding the need for a patient oriented approach to dental service and applying the appropriate technologies to accomplish it.


Expanded FLP toolbox for spatiotemporal protein degradation and transcriptomic profiling in Caenorhabditis elegans.
Control of gene expression in specific tissues and/or at certain stages of development allows the study and manipulation of gene function with high precision. Site-specific genome recombination by the flippase (FLP) and cyclization recombination (Cre) enzymes has proved particularly relevant. Joint efforts of many research groups have led to the creation of efficient FLP and Cre drivers to regulate gene expression in a variety of tissues in Caenorhabditis elegans. Here, we extend this toolkit by the addition of FLP lines that drive recombination specifically in distal tip cells, the somatic gonad, coelomocytes, and the epithelial P lineage. In some cases, recombination-mediated gene knockouts do not completely deplete protein levels due to persistence of long-lived proteins. To overcome this, we developed a spatiotemporally regulated degradation system for green fluorescent fusion proteins based on FLP-mediated recombination. Using 2 stable nuclear pore proteins, MEL-28/ELYS and NPP-2/NUP85 as examples, we report the benefit of combining tissue-specific gene knockout and protein degradation to achieve complete protein depletion. We also demonstrate that FLP-mediated recombination can be utilized to identify transcriptomes in a C. elegans tissue of interest. We have adapted RNA polymerase DamID for the FLP toolbox and by focusing on a well-characterized tissue, the hypodermis, we show that the vast majority of genes identified by RNA polymerase DamID are known to be expressed in this tissue. These tools allow combining FLP activity for simultaneous gene inactivation and transcriptomic profiling, thus enabling the inquiry of gene function in various complex biological processes.


Unmasking of insulin receptors in rat submaxillary gland microsomes: effect of high ionic strength, phospholipase C and S-adenosyl-L-methionine.
The specific binding of [125I]insulin to submaxillary gland microsomes was significantly enhanced by increasing the ionic strength of the incubation medium. This effect was neither related to changes in receptor or hormone degradation nor in the polymerization of the tracer. When equilibrium binding data from competition curves of unlabelled insulin versus [125I]insulin were analyzed, a marked increase in total binding capacity in high ionic strength was observed (from 890 to 2440 fmol/mg protein), with no change in binding affinity. Phospholipase C digestion was also able to increase specific [125I]insulin binding to microsomes. These results suggest the presence of masked receptors in submaxillary gland microsomes. Methylation of rat submaxillary gland microsomes by using S-adenosyl-L-methionine as the methyl donor significantly increased [125I]insulin binding. Scatchard analysis of the equilibrium binding data showed that addition of S-adenosyl-L-methionine (0.46 mM) to microsomes resulted in an enhancement of the total binding capacity (from 990 to 1520 fmol/mg protein) with no change in the affinity constants, which suggests the exposure of masked insulin receptors under such conditions. Both the methyl group incorporation into membrane phospholipids and the effect on insulin binding were dependent on the S-adenosyl-L-methionine concentration used and were partially suppressed in the presence of S-adenosyl-L-homocysteine, a specific competitive inhibitor of the methyltransferases activity. When microsomes were treated with S-adenosyl-L-[methyl-3H]methionine, the 3H-labelled methyl groups incorporated were found mainly in the lipid fraction associated to phosphatidylcholine, suggesting in this case that the unmasking of insulin receptors could be a consequence of alterations produced in membrane composition. The effects of phospholipase C, S-adenosyl-L-methionine and high ionic strength on insulin binding were not additive, suggesting that these procedures unmask receptors from the same pool.


Computational modeling of axonal microtubule bundles under tension.
Microtubule bundles cross-linked by tau protein serve a variety of neurological functions including maintaining mechanical integrity of the axon, promoting axonal growth, and facilitating cargo transport. It has been observed that axonal damage in traumatic brain injury leads to bundle disorientation, loss of axonal viability, and cognitive impairment. This study investigates the initial mechanical response of axonal microtubule bundles under uniaxial tension using a discrete bead-spring representation. Mechanisms of failure due to traumatic stretch loading and their impact on the mechanical response and stability are also characterized. This study indicates that cross-linked axonal microtubule bundles in tension display stiffening behavior similar to a power-law relationship from nonaffine network deformations. Stretching of cross-links and microtubule bending were the primary deformation modes at low stresses. Microtubule stretch was negligible up to tensile stresses of ∼1 MPa. Bundle failure occurred by failure of cross-links leading to pull-out of microtubules and loss of bundle integrity. This may explain the elongation, undulation, and delayed elasticity of axons following traumatic stretch loading. More extensively cross-linked bundles withstood higher tensile stresses before failing. The bundle mechanical behavior uncovered by these computational techniques should guide future experiments on stretch-injured axons.


The specific detection of foot-and-mouth disease virus whole particle antigen (140S) by enzyme labelled immunosorbent assay.
A solid-phase micro-enzyme-labelled immunosorbent assay (ELISA) using guinea pig antiserum against purified (140S) inactivated foot-and-mouth disease (FMD) virus has been used in a sandwich technique to specifically measure 140S virus in the presence of 12S material.


Distribution of fluoroquinolones in the two aqueous compartments of Escherichia coli.
The double-layered cell envelope of Gram-negative bacteria and active drug efflux present a formidable barrier for antimicrobial compounds to penetrate. Fluoroquinolones are among the few classes of antimicrobials that are clinically useful in the treatment of Gram-negative bacterial infection. Previous studies on fluoroquinolone accumulation measured total bacteria associated compounds, rather than the cytoplasmic accumulation. Fluoroquinolones target the type II topoisomerases in the cytoplasm. Thus, the cytoplasmic accumulation is expected to be more relevant to the potency of the drugs. Here, we fractionated and measured the concentration of nine fluoroquinolone compounds in the periplasm and the cytoplasm of two strains of E. coli cells, a parent strain and its isogenic efflux-deficient tolC knockout strain. The potency of the drugs was determined using the minimum inhibitory concentration (MIC) assay. We found that all fluoroquinolones tested accumulated at much higher concentrations in the periplasm than in the cytoplasm. The periplasmic concentrations were 2-15 folds higher than the cytoplasmic concentration, while the actual distribution ratio varies drastically among the compounds tested. Good correlation between the MIC and the cytoplasmic accumulation, but not whole cell accumulation, was observed using a pair of isogenic wild type and drug-efflux deficient strains.


Disability in multiple sclerosis: when synaptic long-term potentiation fails.
Clinical expression of brain damage varies over time and among individuals. This is particularly evident in Multiple Sclerosis (MS) where the expression clinico-radiological paradox has been coined to indicate the weak association between common neuroradiological markers of MS and clinical disability. Here we will review available data suggesting a possible role of adaptive synaptic long-term potentiation (LTP) in the clinical course of MS. We propose that the capacity of the brain to potentiate synaptic excitability in a long-lasting way is the brain's core adaptive property to bridge neuronal damage and clinical expression in multiple sclerosis. LTP, in fact, consists in the strengthening of synaptic communication between two connected neurons, and is virtually able therefore to restore membrane excitability of neurons that have lost part of their synaptic inputs. Recent studies have shown that cortical LTP reserve, explored through transcranial magnetic stimulation (TMS), contrasts disability progression in MS. Furthermore, promotion of cortical LTP through TMS induces acute cortical remapping and ameliorates motor symptoms in MS and in other neurological disorders.


Multi-step-ahead and interval carbon price forecasting using transformer-based hybrid model.
Accurate and stable carbon price forecasts serve as a reference for assessing the stability of the carbon market and play a vital role in enhancing investment and operational decisions. However, realizing this goal is still a significant challenge, and researchers usually ignore multi-step-ahead and interval forecasting due to the non-linear and non-stationary characteristics of carbon price series and its complex fluctuation features. In this study, a novel hybrid model for accurately predicting carbon prices is proposed. The proposed model combines multi-step-ahead and interval carbon price forecasting based on the Hampel identifier (HI), time-varying filtering-based empirical mode decomposition (TVFEMD), and transformer model. First, HI identifies and corrects outliers in carbon price. Second, TVFEMD decomposes carbon price into several intrinsic mode functions (imfs) to reduce the non-linear and non-stationarity of carbon price to obtain more regular features in series. Next, these imfs are reconstructed by sample entropy (SE). Subsequently, the orthogonal array tuning method is used to optimize the transformer model's hyperparameters to obtain the optimal model structure. Finally, after hyperparameter optimization and quantile loss function, the transformer is used to perform multi-step-ahead and interval forecasting on each part of the reconstruction, and the final prediction result is obtained by summing them up. Five pilot carbon trading markets in China were selected as experimental objects to verify the proposed model's prediction performance. Various benchmark models and evaluation indicators were selected for comparison and analysis. Experimental results show that the proposed HI-TVFEMD-transformer hybrid model achieves an average MAE of 0.6546, 1.3992, 1.6287, and 2.2601 for one-step, three-step, five-step, and ten-step-ahead forecasting, respectively, which significantly outperforms other models. Furthermore, interval forecasts almost always have a PICI above 0.95 at a confidence interval of 0.1, thereby indicating the effectiveness of the hybrid model in describing the uncertainty in the forecasts. Therefore, the proposed hybrid model is a reliable carbon price forecasting tool that can provide a dependable reference for policymakers and investors.


Experimental model of trigger finger through A1 pulley constriction in a human cadaveric hand: a pilot study.
Although it can be reasonably assumed that trigger digits occur as the result of a size mismatch in the pulley-tendon system, it is unclear whether locking, histological changes, and nodule formation occur owing to an intrinsically too small pulley or an enlarged digital flexor tendon. Our purposes in this feasibility study were to (1) create a model of trigger digit by pulley constriction in nonpreserved human tissue, (2) measure the change in work of flexion as the force of pulley constriction increased, (3) compare the work of flexion between nontriggering and triggering conditions, and (4) determine whether triggering can occur at the A2, A3, and A4 pulleys under similar conditions. Using a tensiometer, we studied the work of flexion in 4 fingers (thumb, index, middle, and ring) in a human cadaveric hand. The load of flexion was measured as the A1 to A4 pulleys were incrementally constricted in order to induce triggering. Work of flexion was analyzed for differences among trial conditions. Triggering was successfully induced in all 4 digits through constriction of the A1 pulley. No triggering occurred in any of the A2, A3, or A4 pulley systems in this model. We successfully created a trigger model in a human cadaveric hand. Our results demonstrate that the A1 pulley can cause triggering from manual constriction of the pulley alone. A trigger model such as this may allow investigations of pathophysiology, and this may result in novel treatment strategies and modalities.


Sexual differentiation of the hypothalamus in gonadal agenesis and testicular feminization.
Cyclical hypothalamic function was investigated in three patients with an XY karyotype and female external genitalia; in one of them we diagnosed gonadal agenesis, and in the other two testicular feminization. We studied the effect of estradiol and progesterone on gonadotropin release. The patient with gonadal agenesis had cyclical hypothalamic function, but this cyclical function was suppressed in the patients with testicular feminization in whom no LH secretion could be provoked by steroid stimulation. These observations support the concept that hypothalamic sexual differentiation is due to testosterone (which is locally converted to estradiol in the hypothalamus).


Soluble human interleukin-6-receptor modulates interleukin-6-dependent N-glycosylation of alpha 1-protease inhibitor secreted by HepG2 cells.
Interleukin-6 (IL-6) induces changes in gene expression and the N-glycosylation pattern of acute-phase proteins in hepatocytes. IL-6 exerts its action via a cell surface receptor complex consisting of an 80 kDa IL-6 binding protein (gp80) and a 130 kDa glycoprotein (gp130) involved in signal transduction. A genetically engineered gp80-derived soluble human IL-6-receptor (shIL-6-R) significantly enhanced the IL-6 effect on N-glycosylation changes (revealed by reactivity with the lectin-concanavalin A) of a1-protease inhibitor (PI) secreted by human hepatoma cells (HepG2). Stable transfection of IL-6-cDNA into HepG2 cells (HepG2-IL-6) resulting in constitutive secretion of 2 micrograms of IL-6 per 10(6) cells in 24 h led to a down-regulation of surface-bound gp80 and subsequent homologous desensitization of HepG2-IL-6 cells towards IL-6. Soluble human IL-6-R functionally substituted membrane-bound gp80 resulting in a reconstitution of responsiveness of HepG2-IL-6 cells.


Cell interactions and motility in human lung tumor cell lines HS-24 and SB-3 under the influence of extracellular matrix components and proteinase inhibitors.
The human NSCLC cell lines HS-24 (squamous cell carcinoma) and SB-3 (metastasis derived from an adenocarcinoma) were investigated in respect to cell interactions, motility and invasive properties. HS-24 revealed high self adhesion capacity. Testing the interactions with collagens type I/III or IV, laminin and fibronectin by adhesion, non directional motility and haptotaxis assays, tight interactions and stimulation, particularly with collagen type I/III, was detected. Proteinase inhibitors (E64, Stefin A or leupeptin) revealed a slightly negative influence. Invasion in vitro of lung explants was reduced by leupeptin in a dose dependent manner and slightly increased by plasmin. SB-3 cells revealed low self adhesion. As judged from interaction with fibronectin, these cells have low integrin receptor concentrations and thus reduced adhesiveness to extracellular matrix. Collagen type I/III was inhibitory for undirectional motility and not permissive for haptotaxis. Therefore, it may play a restrictive role during the spread in vivo of these cells. Colonization of lung explants was low and was not influenced by cathepsin B proteinase inhibitors. The results emphasize a particular role of collagens for primary site tumor and metastasis development.


Plasma pharmacokinetics of (poly)phenol metabolites and catabolites after ingestion of orange juice by endurance trained men.
The health benefits of orange juice (OJ) consumption are attributed in part to the circulating flavanone phase II metabolites and their microbial-derived ring fission phenolic catabolites. The present study investigated these compounds in the bloodstream after acute intake of 500 mL of OJ. Plasma samples obtained at 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h after OJ intake were analysed by HPLC-HR-MS. Eleven flavanone metabolites and 36 phenolic catabolites were identified and quantified in plasma. The main metabolites were hesperetin-3'-sulfate with a peak plasma concentration (Cmax) of 80 nmol/L, followed by hesperetin-7-glucuronide (Cmax 24 nmol/L), hesperetin-3'-glucuronide (Cmax 18 nmol/L) and naringenin-7-glucuronide (Cmax 21 nmol/L). Among the main phenolic catabolites to increase in plasma after OJ consumption were 3'-methoxycinnamic acid-4'-sulfate (Cmax 19 nmol/L), 3-hydroxy-3-(3'-hydroxy-4'-methoxyphenyl)propanoic acid (Cmax 20 nmol/L), 3-(3'-hydroxy-4'-methoxyphenyl)propanoic acid (Cmax 19 nmol/L), 3-(4'-hydroxyphenyl)propanoic acid (Cmax 25 nmol/L), and 3-(phenyl)propanoic acid (Cmax 19 nmol/L), as well as substantial amounts of phenylacetic and hippuric acids. The comprehensive plasma pharmacokinetic profiles that were obtained are of value to the design of future ex vivo cell studies, aimed at elucidating the mechanisms underlying the potential health benefits of OJ consumption. CLINICAL TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT02627547.


Optimal isolation conditions for rainbow trout (Salmo gairdneri) hepatic ribosomes.
1. Isolation conditions for rainbow trout (Salmo gairdneri) liver ribosomes were optimized. 2. Optimal initial buffer (Buffer I) concentrations were 250 mM sucrose, 50 mM Tris (pH 7.6, 25 degrees C), 75 mM KCl, and 5 mM MgSO4.7H2O. 3. Optimal concentrations for post-105 supernatant buffer (Buffer III) were 25 mM Tris (pH 7.6, 25 degrees C), 75 mM KCl, and 8 mM MgSO4.7H2O.


Advanced cancer targeting using aptamer functionalized nanocarriers for site-specific cargo delivery.
The non-specificity of standard anticancer therapies has profound detrimental consequences in clinical treatment. Therapeutic specificity can be precisely achieved using cutting-edge ligands. Small synthetic oligonucleotide-ligands chosen through Systematic evolution of ligands by exponential enrichment (SELEX) would be an unceasing innovation in using nucleic acids as aptamers, frequently referred to as "chemical antibodies." Aptamers act as externally controlled switching materials that can attach to various substrates, for example, membrane proteins or nucleic acid structures. Aptamers pose excellent specificity and affinity for target molecules and can be used as medicines to suppress tumor cell growth directly. The creation of aptamer-conjugated nanoconstructs has recently opened up innovative options in cancer therapy that are more effective and target tumor cells with minor toxicity to healthy tissues. This review focuses on a comprehensive description of the most capable classes of aptamer-tethered nanocarriers for precise recognition of cancer cells with significant development in proficiency, selectivity, and targetability for cancer therapy. Existing theranostic applications with the problems and future directions are also highlighted.


Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review.
To review recent findings concerning Ca(2+) channel subtype/structure/function from electrophysiological and molecular biological studies and to explain Ca(2+) channel diseases and the actions of anesthetics on Ca(2+) channels. The information was obtained from articles published recently and from our published work. Voltage-dependent Ca(2+) channels serve as one of the important mechanisms for Ca(2+) influx into the cells, enabling the regulation of intracellular concentration of free Ca(2+). Recent advances both in electrophysiology and in molecular biology have made it possible to observe channel activity directly and to investigate channel functions at molecular levels. The Ca(2+) channel can be divided into subtypes according to electrophysiological characteristics, and each subtype has its own gene. The L-type Ca(2+) channel is the target of a large number of clinically important drugs, especially dihydropyridines, and binding sites of Ca(2+) antagonists have been clarified. The effects of various kinds of anesthetics in a variety of cell types have been demonstrated, and some clinical effects of anesthetics can be explained by the effects on Ca(2+) channels. It has recently become apparent that some hereditary diseases such as hypokalemic periodic paralysis result from calcium channelopathies. Recent advances both in electrophysiology and in molecular biology have made it possible to clarify the Ca(2+) channel structures, functions, genes, and the anesthetic actions on the channels in detail. The effects of anesthetics on the Ca(2+) channels either of patients with hereditary channelopathies or using gene mutation techniques are left to be discovered.


A novel algorithm to remove electrical cross-talk between surface EMG recordings and its application to the measurement of short-term synchronisation in humans.
Pairs of discharges of single motor units recorded in the same or different muscles often show synchronisation above chance levels. If large numbers of units are synchronous within and between muscles then the synchrony will be measurable in population recordings such as surface EMG. Measuring synchrony between surface EMG recordings has a number of practical and scientific advantages compared with single motor units recorded from intramuscular electrodes. However, the measurement of such synchrony in the time domain between surface EMGs is complicated because the recordings are contaminated by electrical cross-talk. In this study we recorded surface EMG simultaneously from five hand and forearm muscles during a precision grip task. Using a novel 'blind signal separation' algorithm, we were able to remove electrical cross-talk. The cross-talk-corrected EMGs could then be used to assess task-dependent modulation in both oscillatory (15-30 Hz) and non-oscillatory synchrony (all other frequencies). In agreement with previous studies, the oscillatory component was maximal during steady holding but abolished during movement. By contrast, the non-oscillatory component of the EMG synchrony appeared remarkably constant throughout all phases of the task. We conclude that surface EMG recordings can be of considerable use in the assessment of population synchrony changes, providing that electrical cross-talk between nearby channels is removed using a statistical signal processing technique. Our results show a striking difference in the task-dependent modulation of oscillatory and non-oscillatory synchrony between muscles during a dynamic precision grip task.


Vitamin D3 suppresses astrocyte activation and ameliorates coal dust-induced mood disorders in mice.
Pneumoconiosis patients exhibit significantly more anxiety and depression than healthy individuals. However, the mechanism of coal dust-induced anxiety and depression remains unclear. A pneumoconiosis mouse model with anxiety- and depression-like behaviors were established after 28 days of exposure to coal dust. Vitamin D3 treatment (1200 IU/kg/week) was administered intraperitoneally for 3 months starting from the first coal exposure. Tail suspension test (TST), open field test (OFT), and elevated plus-maze (EPM) test were used to assess anxiety- and depression-like behaviors. Theserum concentration of 25(OH)D3 and fibrillary acid protein (GFAP) expression were determined. In addition, the morphology and distribution of GFAP and neurogenic differentiation factor1 expression (NeuroD1) in different cerebral hippocampus were observed. In coal dust-exposed mice, immobility time decreased in OFT and increased in TST,and the frequency of entering the open arm decreased in the EPM compared with the control mice. Coal dust increased hippocampal GFAP expression and astrocyte activation and reduced neurogenic differentiation factor1 expression (NeuroD1). In addition, Vitamin D3 significantly alleviated anxiety- and depressive-like behaviors in TST and EPM test, decreased GFAP expression level, modified hippocampal astrocyte activation pattern, and advanced brain-derived neurotrophic factor (BDNF) distribution and expression in CA1 and CA3 of the hippocampus. Taken together, our results suggest that, by inhibiting the over-activation of astrocytes and increasing BDNF and neuron protection, vitamin D treatment ameliorates coal-dust-induced depressive and anxiety-like behavior, which is the first evidence that vitamin D may be a new approach for treating mood disorders caused by particulate matter.


Allometry of red cell oxygen binding and hematology in larvae of the salamander, Ambystoma tigrinum.
Very few studies have attempted to relate blood characteristics to body mass within, rather than between, species. Thus, respiratory and hematological properties of the blood of larval tiger salamanders (Ambystoma tigrinum) have been measured in animals ranging in body mass from approximately 2 to 112 g. This amphibian species was chosen because larvae of very different body mass may be of similar developmental stage, minimizing interference from ontogenetic factors. Mean corpuscular volume, mean corpuscular Hb, hematocrit, blood Hb concentration, blood O2 capacity and Hill's n were all positively correlated with body mass (P less than 0.005). Blood O2 affinity (P50) and Bohr shift were not significantly correlated with body mass (P greater than 0.20). The findings are discussed in the context of the general effect of body mass upon metabolic rate in vertebrates, as well as environmental and biological factors specific to larvae of the tiger salamander.


Plasma β-amyloid levels in cerebral amyloid angiopathy-associated hemorrhagic stroke.
Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. To analyze β-amyloid (Aβ) species in plasma in order to uncover biological markers that may contribute to improve the diagnosis of CAA in life. We determined the level of Aβ(1-40), Aβ(N-40), Aβ(1-42) and Aβ(N-42) in plasma of CAA-related ICH patients (n = 29) and healthy controls (n = 21) using xMAP® technology. Hemorrhages were identified and classified using a CT scan and brain MRI. Patients were clinically classified as probable or possible CAA according to the Boston criteria. We found that plasma full-length Aβ(1-42) and truncated fragments Aβ(N-42) were higher in probable CAA patients than in controls (p < 0.001 and p = 0.046, respectively), and full-length Aβ(1-40) was selectively elevated in probable CAA compared to possible cases (p = 0.015) and controls (p = 0.005). In addition, plasma Aβ(N-42) levels were also higher in patients that presented multiple lobar macrohemorrhages compared to patients that had one symptomatic hemorrhagic event (p = 0.022), indicating that a certain degree of CAA severity is necessary to show increased Aβ fragments in peripheral circulation. Our results suggest that specific Aβ fragments in plasma might be considered as potential biomarkers for the diagnosis of CAA.


Association between gifts from pharmaceutical companies to French general practitioners and their drug prescribing patterns in 2016: retrospective study using the French Transparency in Healthcare and National Health Data System databases.
To evaluate the association between gifts from pharmaceutical companies to French general practitioners (GPs) and their drug prescribing patterns. Retrospective study using data from two French databases (National Health Data System, managed by the French National Health Insurance system, and Transparency in Healthcare). Primary care, France. 41 257 GPs who in 2016 worked exclusively in the private sector and had at least five registered patients. The GPs were divided into six groups according to the monetary value of the received gifts reported by pharmaceutical, medical device, and other health related companies in the Transparency in Healthcare database. The main outcome measures were the amount reimbursed by the French National Health Insurance for drug prescriptions per visit (to the practice or at home) and 11 drug prescription efficiency indicators used by the National Health Insurance to calculate the performance related financial incentives of the doctors. Doctor and patient characteristics were used as adjustment variables. The significance threshold was 0.001 for statistical analyses. The amount reimbursed by the National Health Insurance for drug prescriptions per visit was lower in the GP group with no gifts reported in the Transparency in Healthcare database in 2016 and since its launch in 2013 (no gift group) compared with the GP groups with at least one gift in 2016 (-€5.33 (99.9% confidence interval -€6.99 to -€3.66) compared with the GP group with gifts valued at €1000 or more reported in 2016) (P<0.001). The no gift group also more frequently prescribed generic antibiotics (2.17%, 1.47% to 2.88% compared with the ≥€1000 group), antihypertensives (4.24%, 3.72% to 4.77% compared with the ≥€1000 group), and statins (12.14%, 11.03% to 13.26% compared with the ≥€1000 group) than GPs with at least one gift between 2013 and 2016 (P<0.001). The no gift group also prescribed fewer benzodiazepines for more than 12 weeks (-0.68%, -1.13% to -0.23% compared with the €240-€999 group) and vasodilators (-0.15%, -0.28% to -0.03% compared with the ≥€1000 group) than GPs with gifts valued at €240 or more reported in 2016, and more angiotensin converting enzyme (ACE) inhibitors compared with all ACE and sartan prescriptions (1.67%, 0.62% to 2.71%) compared with GPs with gifts valued at €1000 or more reported in 2016 (P<0.001). Differences were not significant for the prescription of aspirin and generic antidepressants and generic proton pump inhibitors. The findings suggest that French GPs who do not receive gifts from pharmaceutical companies have better drug prescription efficiency indicators and less costly drug prescriptions than GPs who receive gifts. This observational study is susceptible to residual confounding and therefore no causal relation can be concluded. OSF register OSF.IO/8M3QR.


Risk of Early Rehospitalization for Non-Behavioral Health Conditions Among Adult Medicaid Beneficiaries with Severe Mental Illness or Substance Use Disorders.
The goal was to examine risk factors and expenditures for early rehospitalization (within 30 days of discharge) for non-behavioral health conditions among Medicaid-enrolled Floridians over 8 years. There were 1,689,797 hospitalization episodes with 19% (N = 314,742) resulting in early rehospitalization. Total gross charges for early rehospitalization were over 13 billion dollars. In Cox proportional hazards regression adjusted for demographic and health covariates, drug use disorder was associated with 50% increased risk of early rehospitalization. Having major depressive disorder increased risk by 17%; psychotic disorder, bipolar disorder, and alcohol use disorder increased risk of early rehospitalization slightly by 10, 6, and 6% respectively. The effect of dementia on risk was minimal at 2%. Risk of early rehospitalization decreased by 3.5% per year over the 8 years of the study. Attention to mental health problems, especially drug use disorder, may help further reduce rates of early readmission for non-behavioral health conditions.


Use of Neuromuscular Electrical Stimulation for Abdominal and Quadriceps Muscle Strengthening: A Randomized Controlled Trial.
Radiographic imaging has demonstrated muscle hypertrophy after treatment with noninvasive body contouring devices that target skeletal muscles. This pilot study sought to evaluate whether increased muscle mass translated to improved functional strength and endurance. A prospective, single-center, randomized open-label controlled study included 26 subjects randomized into 3 groups: 2 treatment groups and 1 control group. Both treatment groups received 4 neuromuscular electrical stimulation (NMES) treatments over a 2-week period. Muscle performance testing was conducted at baseline and 2-week and 4-week posttreatment. Anthropometric measurements were assessed at baseline and at 4-week posttreatment. Study participants completed subject satisfaction surveys and a personal experience assessment. Treatment with NMES resulted in statistically significant improvements in abdominal and quadriceps strength and endurance from baseline through 4-week posttreatment. Mean waist circumference decreased and quadriceps circumference increased, both nonsignificantly. Subject satisfaction regarding abdominal and quadriceps strength was reported as "satisfied or very satisfied" in 89% and 92% at 4-week and 8-week posttreatment, respectively. Treatment of the abdomen and quadriceps with NMES leads to significant improvements in muscular strength and endurance.


An evaluation of the accuracy of clinical diagnosis at admission in a population with epidemic meningococcal disease.
The accuracy (sensitivity and positive predictive value) of the clinical diagnosis given by the general practitioner before admission to hospital was evaluated retrospectively in a population with epidemic meningococcal disease. The study population consisted of approximately 32,000 subjects. In a 12-year period, 344 patients were discharged from hospital with CNS infections, 274 of whom were admitted with a diagnosis suspecting a CNS infection. A further 401 patients were admitted with suspicion for, but discharged without a CNS infection. Overall, the sensitivity was 79.7% and the positive predictive value was 40.6%. There were no significant changes in the accuracy during the study. The sensitivity differed significantly between the age groups (P less than 0.001) and was lowest among the adults (15+ years, 67.9%) and the 0-2-year-old children (72.7%). Also among the 0-2 year-olds, the positive predictive value was low (34.1%) and not significant, indicating that it was more difficult to obtain the correct clinical diagnosis in this group.


Single-incision laparoscopic cholecystectomy (SILC) using harmonic scalpel.
Single-incision laparoscopic cholecystectomy (SILC) is emerging as a potentially less invasive alternative to standard laparoscopic cholecystectomy (LC). However, this procedure is technically more complex and time consuming. We present our initial experience with SILC using harmonic ACE (HS-SILC) in an attempt to simplify the procedure. We collected concurrent data on 67 consecutive patients undergoing HS-SILC by a single surgeon in a university-affiliated hospital over a period of 9 mo. From May 2010 to February 2011, 67 consecutive patients underwent an attempted HS-SILC for symptomatic cholelithiasis by a single surgeon, with a success rate of 95.5%. Conversion to a standard LC was necessary in two patients (2.9%), and conversion to an open cholecystectomy was necessary in one patient (1.6%). The average operative time was 36.2 min. No injuries to the common bile duct occurred. Postoperative port site infection occurred in one patient (1.5%). No perioperative deaths occurred. HS-SILC is safe and feasible. It simplifies the procedure and makes operative time less with better cosmetic results and lower rate of conversion to multi-incision LC or open cholecystectomy.


Olanzapine causes a leptin-dependent increase in acetylcholine release in mouse prefrontal cortex.
The atypical antipsychotic olanzapine is used effectively for treating symptoms of schizophrenia and bipolar disorder. Unwanted effects of olanzapine include slowing of the electroencephalogram (EEG) during wakefulness and increased circulating levels of leptin. The mechanisms underlying the desired and undesired effects of olanzapine are poorly understood. Sleep and wakefulness are modulated by acetylcholine (ACh) in the prefrontal cortex, and leptin alters cholinergic transmission. This study tested the hypothesis that olanzapine interacts with leptin to regulate ACh release in the prefrontal cortex. Within/between subjects. University of Michigan. Adult male C57BL/6J (B6) mice (n = 33) and B6.V-Lep(ob) (leptin-deficient) mice (n = 31). Olanzapine was delivered to the prefrontal cortex by microdialysis. Leptin-replacement in leptin-deficient mice was achieved using subcutaneous micro-osmotic pumps. Olanzapine caused a concentration-dependent increase in ACh release in B6 and leptin-deficient mice. Olanzapine was 230-fold more potent in leptin-deficient than in B6 mice for increasing ACh release, yet olanzapine caused a 51% greater ACh increase in B6 than in leptin-deficient mice. Olanzapine had no effect on recovery time from general anesthesia. Olanzapine increased EEG power in the delta (0.5-4 Hz) range. Thus, olanzapine dissociated the normal coupling between increased cortical ACh release, increased behavioral arousal, and EEG activation. Leptin replacement significantly enhanced (75%) the olanzapine-induced increase in ACh release. Replacing leptin by systemic administration restored the olanzapine-induced enhancement of ACh release in the prefrontal cortex of leptin-deficient mouse.


Characterization of tomato zonate spot virus, a new tospovirus in China.
An isolate of a new tospovirus species, causing concentric zoned ringspots on fruits and necrotic lesions on leaves of infected plants, was characterised based on particle morphology, host range and serological properties. The complete nucleotide sequences of large (L), medium (M), and small (S) RNAs of this virus were found to contain 8919, 4945, and 3279 nts respectively. The L RNA encoded the RNA-dependent RNA polymerase (RdRp) (2885 aa, 332.7 kDa). The M RNA encoded a non-structural (NSm) protein (309 aa, 34.4 kDa) and a viral glycoprotein precursor (Gn/Gc) (1122 aa, 127.4 kDa). The S RNA encoded a non-structural protein (NSs) (459 aa, 51.9 kDa) and the nucleocapsid (N) protein (278 aa, 30.6 kDa). This N protein shared amino acid identities of 80.9% with those of calla lily chlorotic spot virus. Our results suggest that the virus studied here belongs to a new tospovirus species, for which the name tomato zonate spot virus is proposed.


Growth factor rescue of cytokine mediated trophoblast apoptosis.
Apoptosis can be induced in cytotrophoblasts and syncytiotrophoblast in culture by a combination of TNF-alpha and IFN-gamma (Yui et al., 1994a; Garcia-Lloret et al., 1996). This apoptotic action of TNF-alpha and IFN-gamma can be inhibited/'rescued' by EGF (Garcia-Lloret et al., 1996). Additional 'survival' factors have been sought which might protect cells against apoptosis induced by TNF-alpha/IFN-gamma. The survival factors investigated were bFGF, IGF-1, PDGF-AA, VEGF and PLGF. These cytokines were chosen specifically because in common with EGF, the receptors for these molecules are all direct protein tyrosine kinases. All the experiments were carried out using a standard cell culture protocol (Yui et al., 1994a, b; Garcia-Lloret et al., 1996). Apoptosis was induced using TNF-alpha/IFN-gamma, and rescue was attempted using the various cytokines. Apoptosis was identified using the TUNEL technique and quantified by counting 3000 cells in each experimental well. As in previous studies EGF produced a complete inhibition of the apoptotic action of TNF-alpha/IFN-gamma. bFGF, IGF-1, and PDGF-AA produced a partial but significant inhibition of the apoptotic action of TNF-alpha/IFN-gamma. VEGF and PLGF in these experiments had no protective effects against TNF-alpha/IFN-gamma induced apoptosis. Previous studies relating to EGF have been confirmed. bFGF, IGF-1, and PDGF have all been shown to provide partial protection against TNF-alpha/IFN-gamma induced apoptosis. VEGF and PLGF did not protect against apoptosis, and the mechanisms of action remain unclear.


Proteomic analysis of oligodendrogliomas expressing a mutant isocitrate dehydrogenase-1.
Gliomas are primary tumors of the human central nervous system with unknown mechanisms of progression. Isocitrate dehydrogenase-1 (IDH1) mutation is frequent in diffuse gliomas such as oligodendrogliomas. To gain insights into the physiopathology of oligodendrogliomas that have a better prognosis than other diffuse gliomas, we combined microdissection, 2-D DIGE and MS/MS focusing on proteome alterations associated with IDH1 mutation. We first compared tumor tissues (TT) and minimally infiltrated parenchymal tissues (MIT) of four IDH1-mutated oligodendrogliomas to verify whether proteins specific to oligodendroglioma tumor cells could be identified from one patient to another. This study resulted in identification of 68 differentially expressed proteins, with functions related to growth of tumor cells in a nervous parenchyma. We then looked for proteins distinctly expressed in TT harboring either mutant (oligodendrogliomas, n=4) or wild-type IDH1 (oligodendroglial component of malignant glio-neuronal tumors, n=4). This second analysis resulted in identification of distinct proteome patterns composed of 42 proteins. Oligodendrogliomas with a mutant IDH1 had noteworthy enhanced expression of enzymes controlling aerobic glycolysis and detoxification, and anti-apoptosis proteins. In addition, the mutant IDH1 migrated differently from the wild-type IDH1 form. Comparative proteomic analysis might thus be suitable to identify proteome alterations associated with a well-defined mutation.


Testosterone modulates cardiac contraction and calcium homeostasis: cellular and molecular mechanisms.
The incidence of cardiovascular disease rises dramatically with age in both men and women. Because a woman's risk of cardiovascular disease rises markedly after the onset of menopause, there has been growing interest in the effect of estrogen on the heart and its role in the pathophysiology of these diseases. Much less attention has been paid to the impact of testosterone on the heart, even though the levels of testosterone also decline with age and low-testosterone levels are linked to the development of cardiovascular diseases. The knowledge that receptors for all major sex steroid hormones, including testosterone, are present on individual cardiomyocytes suggests that these hormones may influence the heart at the cellular level. Indeed, it is well established that there are male-female differences in intracellular Ca(2+) release and contraction in isolated ventricular myocytes. Growing evidence suggests that these differences arise from effects of sex steroid hormones on processes involved in intracellular Ca(2+) homeostasis. This review considers how myocardial contractile function is modified by testosterone, with a focus on the impact of testosterone on processes that regulate Ca(2+) handling at the level of the ventricular myocyte. The idea that testosterone regulates Ca(2+) handling in the heart is important, as Ca(2+) dysregulation plays a key role in the pathogenesis of a variety of different cardiovascular diseases. A better understanding of sex hormone regulation of myocardial Ca(2+) homeostasis may reveal new targets for the treatment of cardiovascular diseases in all older adults.


A 5-year comparison of ED visits by homeless and nonhomeless patients.
A 2005 study examined emergency department (ED) utilization by homeless patients in the United States. Within the following 5 years, unemployment increased by 5%. The objective was to analyze changes in ED utilization between 2005 and 2010 by homeless patients and compare with nonhomeless visits. Data from the 2010 National Hospital Ambulatory Medical Care Survey were evaluated. Approximately 679854 visits were made by homeless patients, the majority of which were made by men (72.3%) and patients between the ages of 45 and 64 (50.5%). Homeless patients were twice as likely to be uninsured. ED visits by homeless patients had increased by 44% during the 5-year period. Arrival to the ED by ambulance increased by 14% between the study years, and homeless patients were less likely to be admitted. The number of visits by homeless patients in the ED increased proportionally to an overall increase in ED visits between 2005 and 2010.


Phosphoric acid functionalized magnetic sorbents for selective enrichment of TiO2 nanoparticles in surface water followed by inductively coupled plasma mass spectrometry detection.
Phosphoric acid functionalized superparamagnetic iron oxide was synthesized, and different adsorption behavior of TiO2 NPs and titanium ions on it was found. By means of dispersion-corrected density functional theory (DFT-D), the adsorption mechanism of TiO2 NPs and titanium ions on the functionalized sorbents was explored, and the difference in the adsorption behavior was attributed to the different deprotonated forms of phosphates and the competitive adsorption of OH- anion with respect to either TiO2 NPs or aqueous titanium ions. Based on the different adsorption performance of phosphoric acid functionalized sorbents for TiO2 NPs and titanium ions under pH 3, a method by combining magnetic solid phase extraction (MSPE) with inductively coupled plasma mass spectrometry (ICP-MS) was established for the selective quantification of trace TiO2 NPs in environmental water. Under the optimal experimental conditions, the detection limit of TiO2 NPs was 17 ng/L with an enrichment factor of 400. The developed MSPE-ICPMS method was applied to the detection of trace TiO2 NPs in the Yangtze River and the East Lake water. Sub μg/L level of TiO2 NPs was found in the tested water samples, and recoveries of 91-110% and 90-110% were obtained for TiO2 NPs at three concentration levels in spiked water samples, respectively. The developed method exhibited high adsorption capacity and low detection limit for target TiO2 NPs, and was demonstrated with great potential for monitoring TiO2 NPs in the environment.


Genotypic and phenotypic diversity of polyhydroxybutyrate (PHB) producing Pseudomonas putida isolates of Chhattisgarh region and assessment of its phosphate solubilizing ability.
A diverse and versatile spectrum of metabolic activities among isolates of fluorescent Pseudomonas putida indicates their adaptability to various niches. These polyhydroxybutyrate producing and phosphate solubilizing isolates showed a high level of functional and genetic versatility among themselves. One of the potential P. putida isolate P132 can contribute as a candidate agent for both biocontrol and PGPR applications. Identified as one of the most efficient PHB producer and phosphate solubilizer, in vitro detection of P132 showed the presence of genes for phenazine, pyrrolnitrin, pyoluteorin and 2,4 diacetylphloroglucinol along with polyhydroxyalkanoate.


Furosemide does not reduce the incidence of postoperative acute kidney injury in adult patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis.
Acute kidney injury (AKI) is a common complication of cardiac surgical patients, the occurrence of which is multifactorial. Furosemide is the most common loop diuretic and widely used in cardiac surgery to reduce fluid overload, increase tubular flow and urine output. It remains unknown whether furosemide affects the incidence or prognosis of cardiac surgery-induced acute kidney injury (CS-AKI). Therefore, the current study was performed to address this question. PubMed, Embase, Scopus, Cochrane Library, and Web of Science databases were searched for relevant studies. Primary outcomes of interest included postoperative CS-AKI incidence, need for renal replacement therapy (RRT) rate. Secondary outcomes of interest included postoperative serum creatinine (Scr) and blood urea nitrogen (BUN) levels, postoperative mechanical ventilation duration (MVD), length of stay (LOS) in intensive care unit (ICU) and in hospital, and mortality. The odds ratio (OR) and/or the weighted mean difference (WMD) with 95% confidence interval (CI) were used to pool the data. Database search yielded six studies including 566 adult patients, and 283 patients were allocated into Group Furosemide and 283 into Group Control (Placebo). Heterogeneity between studies was deemed acceptable, and the publication bias was low. Meta-analysis suggested that furosemide administration in adult cardiac surgical patients had no effect on CS-AKI incidence (n = 4 trials; OR = 0.92; 95% CI: 0.37-2.30; p = .86; I2 = 57%) and need for RRT rate (n = 2 trials; OR = 4.13; 95% CI: 0.44-38.51; p = .21; I2 = 0%). Diversely, furosemide administration in adult cardiac surgical patients significantly decreased postoperative BUN level (n = 3 trials; WMD = 0.71; 95% CI: 0.10-1.33; p = .02; I2 = 0%), postoperative MVD (n = 2 trials; WMD = -3.13; 95% CI: -3.78 to -2.49; p < .00001; I2 = 0%) and postoperative LOS in ICU (n = 3 trials; WMD = -0.47; 95% CI: -0.76 to -0.18; p = .001; I2 = 0%). However, it had no significant impact on postoperative Scr level, postoperative LOS in hospital, and postoperative mortality. This meta-analysis suggested that furosemide administration in adult cardiac surgical patients had no significant effect on CS-AKI incidence, need for RRT rate, postoperative Scr level, LOS in hospital and mortality, but could reduce postoperative BUN level, MVD, and LOS in ICU. As only a limited number of studies were included, these results should be interpreted carefully and cautiously. Future high-quality randomized controlled trials are needed to define the role of furosemide in CS-AKI prevention and management.