CD103+CD11b+ mucosal classical dendritic cells initiate long-term switched antibody responses to flagellin.
Antibody responses induced at mucosal and nonmucosal sites demonstrate a significant level of autonomy. Here, we demonstrate a key role for mucosal interferon regulatory factor-4 (IRF4)-dependent CD103+CD11b+ (DP), classical dendritic cells (cDCs) in the induction of T-dependent immunoglobulin G (IgG) and immunoglobulin A (IgA) responses in the mesenteric lymph node (MLN) following systemic immunization with soluble flagellin (sFliC). In contrast, IRF8-dependent CD103+CD11b- (SP) are not required for these responses. The lack of this response correlated with a complete absence of sFliC-specific plasma cells in the MLN, small intestinal lamina propria, and surprisingly also the bone marrow (BM). Many sFliC-specific plasma cells accumulating in the BM of immunized wild-type mice expressed α4β7+, suggesting a mucosal origin. Collectively, these results suggest that mucosal DP cDC contribute to the generation of the sFliC-specific plasma cell pool in the BM and thus serve as a bridge linking the mucosal and systemic immune system.


[Trends and variation in breast conserving surgery in the southeast and east of the Netherlands over the period 1990-2002].
To give an overview of the trends and variation in breast-conserving surgery in patients with a breast tumour < or = 2 cm (pT1) or > 2 and < or = 5 cm (pT2), treated in general hospitals in the southeast and east of the Netherlands. Descriptive. Data from the regional cancer registries of the Comprehensive Cancer Centre South (CS) and the Comprehensive Cancer Centre Stedendriehoek Twente (CST) were used to study trends and variations in the use of breast-conserving surgery in 12,985 pT1 tumours and 8,893 pT2 tumours in the period 1990-2002. The mean percentage of patients that underwent breast-conserving surgery from 1990-2002 was 54 in the CS region and 43 in the CST region. In patients < 50 years old with a pT1 tumour a decrease in the percentage of breast-conserving surgery from 73 to 64 was seen in the CS region, and in the CST region this percentage decreased from 72 to 51. In pT2 tumours a decrease from 47 to 37 was seen in the CS region and from 34 to 31 in the CST region. In patients of 50 to 69 years of age with a pT1 tumour, the percentage of breast-conserving surgery increased in the CS region from 67 to 74 and in the CST region from 54 to 61. In pT2 tumours it increased from 40 to 44 and from 25 to 37. In patients > or = 70 years the percentage of breast-conserving surgery in pT1 tumours increased from 37 to 59 in the CS region and in the CST region from 42 to 50. In pT2 tumours it increased from 20 to 31 in the CS region whereas it remained 17 in the CST region. The variation in breast-conserving surgery between hospitals in the period 1999-2002 was large. The percentage of breast-conserving surgery in patients with pT1 tumours varied between 47 and 86 in the hospitals in the CS region and between 54 and 71 in the CST region. In patients with a pT2 tumour the percentages varied between 25 and 43 in the CST region and between 16 and 64 in the CS region. More than 20 years after the introduction of breast-conserving surgery a large regional variation still exists in the use of this treatment, in the CS region in particular. There is also wide inter-hospital variation.


Antiproliferative and cytotoxic activities of furocoumarins of Ducrosia anethifolia.
Phytochemical and pharmacological data on Ducrosia anethifolia (DC.) Boiss. (Apiaceae), an Iranian medicinal plant, are scarce; however, furocoumarins are characteristic compounds of D. anethifolia. Our experiments identify the secondary metabolites of D. anethifolia and assess their antitumor and anti-multidrug resistance activities. Pure compounds were isolated from the extract of aerial parts of the plant by chromatographic methods. Bioactivities were tested on multidrug resistant and sensitive mouse T-lymphoma cell lines. The inhibition of the cancer MDR efflux pump ABCB1 was evaluated by flow cytometry (at 2 and 20 µM). A checkerboard microplate method was applied to study the interactions of furocoumarins and doxorubicin. Toxicity was studied using normal murine NIH/3T3 fibroblasts. Thirteen pure compounds were isolated, nine furocoumarins namely, pabulenol (1), (+)-oxypeucedanin hydrate (2), oxypeucedanin (3), oxypeucedanin methanolate (4), (-)-oxypeucedanin hydrate (5), imperatorin (6), isogospherol (7), heraclenin (8), heraclenol (9), along with vanillic aldehyde (10), harmine (11), 3-hydroxy-α-ionone (12) and 2-C-methyl-erythrytol (13). Oxypeucedanin showed the highest in vitro antiproliferative and cytotoxic activity against parent (IC50 = 25.98 ± 1.27, 40.33 ± 0.63 µM) and multidrug resistant cells (IC50 = 28.89 ± 0.73, 66.68 ± 0.00 µM), respectively, and exhibited slight toxicity on normal murine fibroblasts (IC50 = 57.18 ± 3.91 µM). Compounds 2, 3, 5, 7, 10-13 were identified for the first time from the Ducrosia genus. Here, we report a comprehensive in vitro assessment of the antitumor activities of D. anethifolia furocoumarins. Oxypeucedanin is a promising compound for further investigations for its anticancer effects.


Higher prevalence of iron deficiency as strong predictor of attention deficit hyperactivity disorder in children.
It has been reported that ferritin and iron deficiency may be related to the path physiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine the association between iron deficiency and ADHD and the impact and role of iron deficiency on the development of ADHD in children. The study based on the case-control study age- and sex-matched control and conducted at the School Health and Primary Healthcare Clinics, Qatar. A total of 630 children with ADHD aged 5-18 and 630 controls aged 5-18 years old. Sociodemographic and clinical data were collected, including physician diagnosis. The health status of the subjects was assessed by ascertaining clinical presentations and symptoms, family history, body mass index (BMI), iron deficiency, ferritin, serum 25-hydroxyvitamin D, calcium, magnesium, and phosphorus levels. Descriptive, univariate, and multivariate statistical analysis were performed. Mean age (standard deviation [SD] in years) for ADHD and control children were 11.54 (3.83) versus 11.50 (3.62). There were statistically significant differences between ADHD versus control children for vitamin D [16.81 (7.84) vs. 22.18 (9.00) ng/ml], serum iron [82.11 (13.61) vs. 85.60 (12.47) ng/ml], ferritin [36.26 (5.93) vs. 38.19 (5.61) ng/ml], hemoglobin [12.02 (2.13) vs. 12.89 (2.02) g/dL], magnesium [0.82 (0.08) vs. 0.88 (0.06) mmol/L], serum calcium level [2.35 (0.12) vs. 2.39 (0.14) mmol/L], and phosphorous [1.47 (0.30) vs. 1.54 (0.26) mmol/L]. Of total 630 of ADHD children, 116 (18.4%) had severe vitamin D deficiency (<10 ng/ml). Multivariate logistic regression analysis revealed that serum vitamin D level, serum iron, ferritin, serum calcium level, physical activity, nervous behavior, consanguinity, BMI, and child order were considered as the main factors associated with the ADHD after adjusting for age, gender, and other variables. The study indicates that low serum iron, ferritin levels, and vitamin D deficiency may be associated with ADHD.


Unfavorable perceived neighborhood environment associates with less routine healthcare utilization: Data from the Dallas Heart Study.
Neighborhood environment perception (NEP) has been associated with health outcomes. However, little is known about how NEP relates to routine healthcare utilization. This study investigated the relationship between NEP and independent subfactors with healthcare utilization behavior, as measured by self-reported (1) usual source of healthcare and (2) time since last routine healthcare check-up. We used cross-sectional data from the Dallas Heart Study, which features a diverse, probability-based sample of Dallas County residents ages 18 to 65. We used logistic regression modeling to examine the association of self-reported NEP and routine healthcare utilization. NEP was assessed via a questionnaire exploring residents' neighborhood perceptions, including violence, the physical environment, and social cohesion. Routine healthcare utilization was assessed via self-reported responses regarding usual source of care and time since last routine healthcare check-up. The analytic sample (N = 1706) was 58% black, 27% white, 15% Hispanic, 42% male, and had a mean age of 51 (SD = 10.3). Analysis of NEP by tertile demonstrated that younger age, lower income, and lower education were associated with unfavorable overall NEP (p trend <0.05 for each). After adjustment for potential confounders, including neighborhood deprivation, health insurance, disease burden and psychosocial factors, we found that individuals with more unfavorable perception of their physical environment were more likely to report lack of a usual source of care (p = 0.013). Individuals with more unfavorable perception of the neighborhood physical environment or greater neighborhood violence reported longer time periods since last routine visit (p = 0.001, p = 0.034 respectively). There was no relationship between perceived social cohesion and healthcare utilization. Using a multi-ethnic cohort, we found that NEP significantly associates with report of a usual source of care and time since last routine check-up. Our findings suggest that public health professionals should prioritize improving NEP since it may act as barrier to routine preventive healthcare and ideal health outcomes.


Correlation between structural stability of LiBH4 and cation electronegativity in metal borides: an experimental insight for catalyst design.
Nanosized metal borides MBx (M = Mg, Ti, Fe, Si) are found to play an important role in enhancing the hydrogen storage performance of LiBH4 in this work. The hydrogen storage behavior and mechanism of these modified systems are investigated through TPD-MS, XRD, FTIR and SEM characterization methods. By introducing these metal borides into LiBH4 through ball milling, the systems display three dehydrogenation stages disclosing their similarity and distinction. The 1st stage starts at 190 °C, the 2nd stage ranges from 280 °C to 400 °C and the 3rd stage ends at 550 °C with a peak at round 440 °C similar to that of pristine LiBH4. Distinguishing features exist at the 2nd stage revealing the effectiveness of MBx in an order of MgB2 < TiB2 < FeB < SiB4. Significantly, reversibility up to 9.7 wt% is achieved from LiBH4 with assistance of SiB4. The catalytic effect of MBx is influenced by the Pauling electronegativity of M in MBx and the interfacial contact characteristic between LiBH4 and MBx. The larger electronegativity leads to an enhanced catalytic effect and consequently lower temperature at the major stage. In contrast to the components in the solid state, the molten LiBH4 promotes a catalytic effect due to a superior interfacial contact. These results provide an insight into designing high-performance catalysts applied to LiBH4 as a hydrogen storage material.


Chemical-shift tensors of heavy nuclei in network solids: a DFT/ZORA investigation of (207)Pb chemical-shift tensors using the bond-valence method.
Cluster models are used in calculation of (207)Pb NMR magnetic-shielding parameters of α-PbO, β-PbO, Pb3O4, Pb2SnO4, PbF2, PbCl2, PbBr2, PbClOH, PbBrOH, PbIOH, PbSiO3, and Pb3(PO4)2. We examine the effects of cluster size, method of termination of the cluster, charge on the cluster, introduction of exact exchange, and relativistic effects on calculation of magnetic-shielding tensors with density functional theory. Proper termination of the cluster for a network solid, including approximations such as compensation of charge by the bond-valence (BV) method, is essential to provide results that agree with experiment. The inclusion of relativistic effects at the spin-orbit level for such heavy nuclei is an essential factor in achieving agreement with experiment.


Pentobarbital anesthesia modifies pulmonary vasoregulation after hypoperfusion.
Our objectives were 1) to investigate the extent to which the pulmonary vascular response to increasing cardiac index after a period of hypotension and hypoperfusion (defined as reperfusion) measured in conscious dogs is altered during pentobarbital sodium anesthesia, and 2) to determine whether pentobarbital anesthesia modifies autonomic nervous system (ANS) regulation of the pulmonary circulation during reperfusion. Base-line and reperfusion pulmonary vascular pressure-cardiac index (P/Q) plots were generated by stepwise inflation and deflation, respectively, of an inferior vena caval occluder to vary Q in conscious and pentobarbital-anesthetized (30 mg/kg iv) dogs. During pentobarbital anesthesia, controlled ventilation (without positive end-expiratory pressure) allowed matching of systemic arterial and mixed venous blood gases to conscious values. Marked pulmonary vasoconstriction (P less than 0.01) was observed during reperfusion in pentobarbital-anesthetized but not in conscious dogs. Both sympathetic alpha-adrenergic receptor block and total ANS ganglionic block attenuated, but did not abolish, the pulmonary vasoconstriction during reperfusion in pentobarbital-anesthetized dogs. Neither sympathetic beta-adrenergic receptor block nor cholinergic receptor block enhanced the magnitude of the pulmonary vasoconstrictor response to reperfusion during pentobarbital anesthesia. Thus, in contrast to the conscious state, the pulmonary vascular response to reperfusion is characterized by active, non-flow-dependent pulmonary vasoconstriction during pentobarbital anesthesia. This response is primarily, but not exclusively, mediated by sympathetic alpha-adrenergic vasoconstriction and is not offset by either sympathetic beta-adrenergic or cholinergic vasodilation. These results indicate, that, compared with the conscious state, pentobarbital anesthesia modifies pulmonary vasoregulation, during reperfusion following hypotension and hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)


ADDITIVE INHERITANCE OF SERUM CHOLESTEROL LEVEL IN MICE.
Serum cholesterol level ( SCL) was measured in 600 mice belonging to five inbred strains of mice ( DBAIIJ, C57BL/ 1OJ, A/ J, C3H/ HeJ, and BALBI cJ) and all 20 F, hybrids resulting from the systematic crossing of the inbreds. Diet was kept constant and its effect on SCL was not evaluated. The data show that in mice, the mode of inheritance of SCL is neither dominant nor recessive, but is intermediate. A simple additive model accounts for the results: the SCL is a linear function of the SCL of the mother, the SCL of the sire, and the sex of the subject; the three factors do not interact.


Health care resource allocation: is the threshold rule good enough?
We review the foundations of resource allocation rules based on cost-effectiveness information. Comprehensive approaches, where a total budget is allocated in one go, require estimation of the costs and effects of all available health care programmes, which is unlikely to be practical. A common alternative is to assess individual programmes against a cost-effectiveness threshold. This has been shown to be efficient if the threshold is well calibrated and all programmes can be wholly or partially implemented with constant returns to scale. We discuss the feasibility of these assumptions, and the effects of relaxing them, concluding that programme indivisibility is unlikely to be a serious problem at a national level, but that miscalibration of the threshold and non-constant returns to scale might be. A rule that avoids these difficulties has been proposed previously: a new programme should only be implemented if it can be funded by cancelling another less effective programme. This could never reduce efficiency, unlike the threshold rule, though we show that it might sometimes fail to recommend an efficiency-improving change. We suggest a refinement of this reallocation rule based on explicit estimation of the costs and effects of partial implementation of the programmes under review. Research is required to assess the practicality of this option.


Stability of polyphenols and carotenoids in strawberry and peach yoghurt throughout in vitro gastrointestinal digestion.
The aim of this research was to evaluate the influence of in vitro gastrointestinal digestion on the stability and bio-accessibility of phenolic compounds and carotenoids, as well as on the antioxidant activity in strawberry and peach enriched yoghurt. The radical scavenging capacity of strawberry and peach yoghurt was 480 and 550% higher, respectively, at the level of the intestine than in fruit yoghurt not subjected to digestion. In strawberry the amount of bio-accessible anthocyanins increased during gastric digestion and the transition to the intestinal compartment produced a decrease in all the analyzed classes of polyphenols, being more pronounced in pelargonidin-3-glucoside (65%) and pelargonidin-3-rutinoside (58%). In peach the (+)-catechin content strongly decreased (80%), and neochlorogenic, chlorogenic acid, rutin and the carotenoid zeaxanthin decreased at lower levels, between 32-45%, while β-carotene was rather stable under gastric conditions (increased by 12%) during intestinal digestion. Despite the decrease in the concentration of these bioactive compounds after being subjected to in vitro gastrointestinal digestion, results suggest that fruit yoghurt is an important source of bio-accessible polyphenols and carotenoids and that despite some losses induced by digestion conditions, it still releases relevant amounts at the level of the intestine to be absorbed and to promote health benefits.


Assessing Direct and Residual Effects of Cover Crops on the Soybean Cyst Nematode, Heterodera glycines.
Greenhouse experiments were conducted to determine if cover crops directly decrease population densities of the soybean cyst nematode (SCN), Heterodera glycines, and/or have residual effects on reproduction of the nematode on soybean (Glycine max). Population densities of SCN were not significantly decreased by nine cover crop plants or three cover crop mixes compared with a non-planted soil control in a repeated 60-day-long greenhouse experiment. When susceptible soybeans were grown in the soils after cover crop growth, fewer SCN females formed after three annual ryegrass (Lolium multiflorum) cultivars (Bounty, King, and RootMax), the Daikon radish (Raphanus sativus var. longipinnatus) cultivar CCS779, Kodiak mustard (Brassica juncea), and a mix containing cereal rye, crimson clover (Trifolium incarnatum), plus Daikon radish (cultivars not stated) compared with following the non-planted control. In another repeated experiment, cover crops were grown for 56 days in SCN-infested soil in the greenhouse then exposed to Iowa winter conditions for 28 days to simulate winter termination of the plants. One treatment, a cover crop mix containing 'Bounty' annual ryegrass plus 'Enricher' Daikon radish, had a decrease in SCN population density greater than the non-planted control at the end of the experiment. Significantly fewer SCN females formed on soybeans grown after several cover crops, including the three annual ryegrass cultivars that had the suppressive residual effects in the first experiment. In summary, there were no cover crop treatments that consistently decreased SCN population densities across experiments, and only one cover crop treatment in one experiment significantly reduced SCN population densities more than a non-planted soil control. However, there was a somewhat consistent, adverse, residual effect of cover crops on reproduction of SCN on susceptible soybeans after growth of multiple cover crops.


Effects of reserpine on extracellular caudate dopamine and hippocampus norepinephrine responses to amphetamine and cocaine: mechanistic and behavioral considerations.
Following reserpine pretreatment to disrupt vesicular stores of dopamine and norepinephrine, in vivo microdialysis was used in behaving rats to evaluate the role of vesicles in the neurochemical and behavioral responses to amphetamine and cocaine. Reserpine (2.5 mg/kg, 24 hr) completely prevented the hippocampus norepinephrine responses to 20 mg/kg of cocaine and to 0.5, 1.25 and 5.0 mg/kg of amphetamine. Likewise, reserpine almost completely abolished the caudate putamen dopamine response to cocaine. In contrast, the effect of reserpine on the amphetamine-induced dopamine response varied as a function of amphetamine dose. Although the dopamine response to 1.25 mg/kg of amphetamine was unchanged by reserpine pretreatment, the dopamine responses to both the lowest (0.5 mg/kg) and highest (5.0 mg/kg) doses of amphetamine were significantly attenuated by about 65% and 50%, respectively. These results indicate that the norepinephrine response to amphetamine is dependent on vesicular stores of transmitter at all doses of the drug. However, although amphetamine can release dopamine from a reserpine-resistant (non-vesicular) pool, it also appears that this response partially depends on vesicular stores, especially at low and high doses of drug. Concomitant behavioral assessments revealed that the behavioral responses to cocaine and the lowest dose of amphetamine, like the dopamine responses, were significantly suppressed by reserpine pretreatment. In contrast, at the intermediate dose of amphetamine, stereotypies were significantly enhanced. These altered behavioral profiles are discussed in terms of a balance between increases in both dopamine and norepinephrine produced by amphetamine.


Faculty practice plans: the organization and characteristics of academic medical practice.
The contemporary academic medical center is a complex organization providing medical and other professional health education, biomedical and behavioral research, and a comprehensive range of patient care services. This paper presents data from the Association of American Medical Colleges' 1989 survey of 125 member faculty practice plans. The survey data showed that 62% of the 74 responding plans were units or associations within the medical school corporate structure. Plans were organized along a broad continuum from the autonomous, departmental model with decentralized governance and management to the group model with centralized governance and management. The growth of managed care, increased competition, and a greater reliance by the medical school on clinical practice income as a financing source are causing the practice plan to expand beyond billing of professional fees. The survey data showed that 75% of the practice plans operated satellite centers, and 61% planned to build new ambulatory care facilities in order to expand and improve services to patients. The practice plans also have adapted to changes in third-party reimbursement and are establishing mechanisms to negotiate managed care contracts involving multiple clinical departments to increase referrals and maintain patient shares; 86% of the plans participate in at least one managed-care organization. The role of the practice plan will continue to evolve in response to the needs of the academic medical center for a cooperative and supportive environment in which to conduct its traditional missions of teaching, research, and patient care.


Surface Initiated Polymer Thin Films for the Area Selective Deposition and Etching of Metal Oxides.
The area selective growth of polymers and their use as inhibiting layers for inorganic film depositions may provide a valuable self-aligned process for fabrication. Polynorbornene (PNB) thin films were grown from surface-bound initiators and show inhibitory properties against the atomic layer deposition (ALD) of ZnO and TiO2. Area selective control of the polymerization was achieved through the synthesis of initiators that incorporate surface-binding ligands, enabling their selective attachment to metal oxide features versus silicon dielectrics, which were then used to initiate surface polymerizations. The subsequent use of these films in an ALD process enabled the area selective deposition (ASD) of up to 39 nm of ZnO. In addition, polymer thickness was found to play a key role, where films that underwent longer polymerization times were more effective at inhibiting higher numbers of ALD cycles. Finally, while the ASD of a TiO2 film was not achieved despite blanket studies showing inhibition, the ALD deposition on polymer regions of a patterned film produced a different quality metal oxide and therefore altered its etch resistance. This property was exploited in the area selective etch of a metal feature. This demonstration of an area selective surface-grown polymer to enable ASD and selective etch has implications for the fabrication of both micro- and nanoscale features and surfaces.


[Torsion and seminoma in a cryptorchid testis].
Presentation of one case of seminoma on cryptorchid testicle which presented with torsion of spermatic cord clinically mimicking an inguinal incarcerated hernia. Despite the infrequency of the picture, the high association rate of neoplastic disease in cryptorchid testis which become twisted and force the adoption of oncological criteria for their treatment is highlighted.


Macular Vessel Density in Diabetic Retinopathy Patients: How Can We Accurately Measure and What Can It Tell Us?
Diabetic retinopathy is one of the leading causes of blindness worldwide. Optical coherence tomography angiography (OCTA) is a non-invasive technology that provides depth-resolved images of the chorioretinal vasculature and allows for the understanding of the changes in vasculature with diabetic retinopathy. Not only can it provide qualitative information, but OCTA can also provide quantitative information about the vasculature in patients with diabetic retinopathy. Macular vessel density is one of the quantitative metrics that can be obtained from OCTA images. This is a repeatable and non-subjective measurement that can provide valuable insight into the pathophysiology of diabetic retinopathy. In this non-systematic review, the measurement of macular vessel density in diabetic retinopathy and the reasons for its importance in the diagnosis and management of patients with diabetes and varying severities of diabetic retinopathy is discussed.


Validation of Structural Equation Modeling Methods for Functional MRI Data Acquired in the Human Brainstem and Spinal Cord.
Structural equation modeling (SEM) provides a means of investigating relationships between blood oxygenation level-dependent (BOLD) signal changes in functional MRI data across neuroanatomical regions. The objectives of this study were to demonstrate adapted SEM methods for the brainstem and spinal cord, validate statistical methods and appropriate statistical thresholds, and test the methods with existing data. SEM methods were applied using an anatomical model of regions of the thalamus, brainstem, and spinal cord that are involved with pain processing. Statistical distributions (Z-scores), significance thresholds, and corrections for multiple comparisons were determined from repeated simulations using "null" data sets. SEM analyses were then applied to data from prior studies involving noxious stimulation in healthy participants. Z-score distributions were observed to vary with the number of source regions modeled, the number of time points (volumes) included in the analysis, and the time span (epoch) used for dynamic analyses. Appropriate choices of statistical thresholds and corrections for multiple comparisons were demonstrated. The results reveal consistent network features across/within studies, as well as dependences on study conditions. They show the effectiveness of a SEM method for functional MRI data from the brainstem and spinal cord.


Preliminary evidence for an association of Epstein-Barr virus with pre-ulcerative oral lesions in patients with recurrent aphthous ulcers or Behçet's disease.
In this study we used the polymerase chain reaction (PCR), slot blot and Southern blot hybridization, direct sequencing and in situ hybridization (ISH) to show the possible presence of EBV-DNA in pre-ulcerative oral aphthous lesions of patients with recurrent aphthous ulcers (RAU) or Behçet's disease (BD). For this purpose, formalin-fixed biopsy specimens were obtained from 13 pre-ulcerative oral aphthous lesions of nine RAU and four BD patients. Five specimens of normal oral mucosa (NOM) from five normal control subjects and 10 specimens of oral erosive or ulcerative lesions from 10 patients with erosive lichen planus (ELP) were also included. EBV-DNA was detected by PCR in 5 of the 13 (38.5%) pre-ulcerative oral aphthous lesions, two from RAU patients and three from BD patients. However, no EBV-DNA was demonstrated in five NOM specimens from normal control subjects and in 10 specimens of oral lesions from ELP patients. EBV-DNA was also demonstrated in patients' peripheral blood lymphocytes and/or plasma, suggesting that the lymphocytes may be the reservoir of latent EBV infection and there is EBV shedding in the plasma. EBV-DNA was detected by ISH in only one PCR-positive case; the reaction product was found to deposit on the nuclei of some of the epithelial cells and lymphocytes. By immunohistochemistry, expression of Epstein-Barr nuclear antigen and EBV/C3d receptors was also noted in some of the epithelial cells and lymphocytes in this ISH-positive case. Therefore, we suggest that the epithelial cells of pre-ulcerative oral aphthous lesions may be infected by EBV through EBV-infected lymphocytes; also, the cytotoxic T lymphocyte-induced lysis of the EBV-infected epithelial cells, but not the virus-induced cytolysis, may be the main mechanism causing oral ulcer formation. Our data provide preliminary evidence for an association of EBV with pre-ulcerative oral aphthous lesions in RAU and BD patients.


A study of recent life events and their role in the precipitation of mania.
The present study of fifty patients was aimed at determining the prevalence and nature of recent life events and their role in the precipitation of mania. The role of other factors like family history of psychiatric illness and personality temperament were also taken into account. The study showed that 54% of patients with manic episodes had life events in the preceding one month. The commonest type of life event perceived was a financial problem, large loan, marital and family conflicts and damage to property or crops. Perception of life events had a statistically significant relationship with family history of mental illness and educational status.


Predictability of the Call Triage Protocol to Detect if Dispatchers Should Activate Community First Responders.
Shortening response time to an emergency call leads to the success of resuscitation by chest compression and defibrillation. However, response by ambulance or fire truck is not fast enough for resuscitation in Japan. In rural areas, response times can be more than 10 minutes. One possible way to shorten the response time is to establish a system of first responders (eg, police officers or firefighters) who are trained appropriately to perform resuscitation. Another possible way is to use a system of Community First Responders (CFRs) who are trained neighbors. At present, there are no call triage protocols to decide if dispatchers should activate CFRs. The aim of this study was to determine the predictability to detect if dispatchers should activate CFRs. Two CFR call triage protocols (CFR protocol Ver.0 and Ver.1) were established. The predictability of CFR protocols was examined by comparing the paramedic field reports. From the results of sensitivity of CFR protocol, the numbers of annual CFR activations were calculated. All data were collected, prospectively, for four months from October 1, 2012 through January 31, 2013. The ROC-AUC values appear slightly higher in CFR protocol Ver.1 (0.857; 95% CI, 79.8-91.7) than in CFR protocol Ver.0 (0.847; 95% CI, 79.0-90.3). The number of annual CFR activations is higher in CFR protocol Ver.0 (7.47) than in CFR protocol Ver.1 (5.45). Two call triage protocols have almost the same predictability as the Medical Priority Dispatch System (MPDS). The study indicates that CFR protocol Ver.1 is better than CFR protocol Ver.0 because of the higher predictability and low number of activations. Also, it indicates that CFRs who are not medical professionals can respond to a patient with cardiac arrest.


Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.
Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC(50) = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.


Distribution of genes encoding resistance to macrolides, lincosamides and streptogramins among clinical staphylococcal isolates in a Turkish university hospital.
This study investigated the prevalence of genes encoding resistance to macrolides, lincosamides and streptogramins (MLS(B)) among staphylococci in a series of 301 erythromycin-resistant clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci (CoNS). Erythromycin-resistance phenotypes were determined according to Clinical and Laboratory Standards Institute guidelines and specific resistance genes erm(A), erm(B), erm(C), msr(A) and msr(B) were identified using polymerase chain reaction. Two hundred of 301 (66.5%) erythromycin-resistant staphylococcal isolates exhibited resistance to MLS(B) antibiotics. Of these, 127 (63.5%) exhibited a cMLS(B) resistance phenotype (resistant to both erythromycin and clindamycin), whereas 73 (36.5%) expressed the iMLS(B) resistance phenotype (resistant to erythromycin and susceptible to clindamycin). The most prevalent resistance determinants were erm(A) (62%) among S. aureus and erm(C) (30%) among CoNS isolates. Combinations of resistance mechanisms were rarely seen, and occurred most often in oxacillin-resistant isolates. The results of the present study support the idea that there are geographical differences in the prevalence of erythromycin resistance mechanisms among staphylococci, therefore local surveillance studies are important tools for guiding therapy and in the promotion of judicious use of antimicrobial agents.


[I.M.V.-ventilation-techniques. Special considerations and problems of their application (author's transl)].
The clinical significance of I.M.V.-technique with or without C.P.A.P. are shown. The influence of different I.M.V.-technique on spontaneous respiration and lung ventilation is analyzed. Patient-synchronized techniques especially S.-I.M.V. or E.S.-I.M.V. prooved to be superior. Respiratory-physiological and technical recommendation for I.M.V.-arrangements are given and common devices of the literature analyzed. By these examples individual as well as commercially available devices can be critically evaluated for practical use and safety.


The effects in rats of lisdexamfetamine in combination with olanzapine on mesocorticolimbic dopamine efflux, striatal dopamine D2 receptor occupancy and stimulus generalization to a D-amphetamine cue.
The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine's ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine.


Theft of Controlled Substances in Long-Term Care Homes: An Exploratory Study.
The theft of controlled substances has been studied in the community and healthcare settings including hospitals, pharmacies, hospice, and pain clinics. However, research on these thefts in long-term care homes has yet to be published. This exploratory study makes first steps toward bridging this gap. Using 107 Minnesota Department of Health's investigation reports substantiated as "drug diversion" between 2013 and 2021 in assisted living residences and nursing homes, we found that 11,328.5 tablets were stolen from 368 residents (97.5% were controlled substances), with over 30 tablets stolen per resident. We also identified the types of medications stolen, duration of theft, extent to which nurses stole the medications or were those initially suspecting thefts, and the role of surveillance cameras in confirming allegations. The findings could raise awareness to this form of elder mistreatment in long-term care homes and call for action to address it.


Inhibition of lipogenesis by halothane in isolated rat liver cells.
1. Halothane at clinically effective concentrations [2.5 and 4% (v/v) of the gas phase of the incubation flask] was found to inhibit significantly lipogenesis from endogenous substrates, e.g., glycogen, or from added lactate plus pyruvate. This was accompanied by a decrease in the ratio of the free [NAD+]/[NADH] of the mitochondrion and the cytoplasm, as shown by the [3-hydroxybutyrate]/[acetoacetate] ratio and the [lactate]/[pyruvate] ratio. 2. Acetoacetate or pyruvate decreased the inhibitory effect of halothane and restored lipogenesis to control rates. They were reduced rapidly by 3-hydroxybutyrate dehydrogenase or lactate dehydrogenase respectively, with the concomitant oxidation of NADH and the generation of NAD+. 3. These results suggest that the mechanism by which halothane inhibits lipogenesis from glycogen or lactate is by inhibition of the oxidation of NADH; this results in inhibition of flux of carbon through pyruvate dehydrogenase and a shortage of acetyl-CoA for fatty acid synthesis. Thus when NADH acceptors are added in the presence of halothane, the concentration of mitochondrial NAD+ is raised so that the flux of carbon through pyruvate dehydrogenase increases and lipogenesis is restored.


Fish and Clips: A Convenient Strategy to Identify Tyrosinase Substrates with Rapid Activation Behavior for Materials Science Applications.
Peptides with suitable substrate properties for a specific tyrosinase are selected by combinatorial means from a one-bead-one-compound (OBOC) peptide library. The identified sequences exhibit tyrosine residues that are rapidly oxidized to 3,4-dihydroxyphenylalanine (Dopa), making the peptides interesting for enzyme-activated adhesives. The selection process of peptides involves tyrosinase oxidation of tyrosine-bearing sequences on a solid support, yielding dopaquinone residues (fish from the sequence pool), to which thiol-functional fluorescent probes attach by Michael-reaction (clip to mark). Labeled supports are isolated and sequence readout is feasible by MALDI-TOF-MS/MS to reveal peptides, while activation kinetics as well as enzyme-activated coating behavior are verifying the proper selection.


Dietary Change during Pregnancy and Women's Reasons for Change.
Women often make dietary changes during pregnancy; however, dietary modifications and reasons for changes are not well studied. We aimed to describe the dietary changes made during pregnancy, describe reasons for dietary changes, and determine what changes aligned with recommendations. Pregnant women (n = 379) recruited to the Alberta Pregnancy Outcomes and Nutrition (APrON) study in 2009/2010 completed a questionnaire in which they described dietary changes made during pregnancy and reasons for those changes. Changes and reasons were coded into categories. Women commonly reported increasing their intake of milk products, fruit, and sweet items and commonly decreased or eliminated intake of caffeine, alcohol, and meats. Women frequently reduced intake of foods for the baby's health and increased foods to satisfy cravings. Changes made commonly aligned with recommendations for caffeine, alcohol intake, food safety, milk and alternatives, and fruit. Changes contrary to recommendations were common for fish and meats. The dietary changes women make during pregnancy appear to reflect women's efforts to balance physiological changes accompanying pregnancy with the desire for healthy pregnancy outcomes. Understanding the reasons behind dietary change during pregnancy will help researchers and health professionals design effective strategies and public health messages to promote healthier pregnancies.


In silico identification of functional divergence between the multiple groEL gene paralogs in Chlamydiae.
Heat-shock proteins are specialized molecules performing different and essential roles in the cell including protein degradation, folding and trafficking. GroEL is a 60 Kda heat-shock protein ubiquitous in bacteria and has been regarded as an important molecule implicated in chronic inflammatory processes caused by Chlamydiae infections. GroEL in Chlamydiae became duplicated at the origin of the Chlamydiae lineage presenting three distinct molecular chaperones, namely the original protein GroEL1 (Ct110), and its paralogous proteins GroEL2 (Ct604) and GroEL3 (Ct755). These chaperones present differential and independent expressions during the different stages of Chlamydiae infections and have been suggested to present differential physiological and regulatory roles. In this comprehensive in silico study we show that GroEL protein paralogs have diverged functionally after the different gene duplication events and that this divergence has occurred mainly between GroEL3 and GroEL1. GroEL2 presents an intermediate functional divergence pattern from GroEL1. Our results point to the different protein-protein interaction patterns between GroEL paralogs and known GroEL protein clients supporting their functional divergence after groEL gene duplication. Analysis of selective constraints identifies periods of adaptive evolution after gene duplication that led to the fixation of amino acid replacements in GroEL protein domains involved in the interaction with GroEL protein clients. We demonstrate that GroEL protein copies in Chlamydiae species have diverged functionally after the gene duplication events. We also show that functional divergence has occurred in important functional regions of these GroEL proteins and that very probably have affected the ancestral GroEL regulatory role and protein-protein interaction patterns with GroEL client proteins. Most of the amino acid replacements that have affected interaction with protein clients and that were responsible for the functional divergence between GroEL paralogs were fixed by adaptive evolution after the groEL gene duplication events.


Experimental demonstration of a defect-tolerant nanocrossbar demultiplexer.
Ultradense memory and logic circuits fabricated at local densities exceeding 100 × 10(9) cross-points per cm(2) have recently been demonstrated with nanowire crossbar arrays. Practical implementation of such nanocrossbar circuitry, however, requires effective demultiplexing to solve the problem of electrically addressing individual nanowires within an array. Importantly, such a demultiplexer (demux) must also be tolerant of the potentially high defect rates inherent to nanoscale circuit fabrication. We have built a 50 nm half-pitch nanocrossbar circuit using imprint lithography and configured it for a demux application. Utilizing a class of Hamming codes in the hardware design, we experimentally demonstrate defect-tolerant demux operations on a 12 × 8 nanocrossbar array with up to two stuck-open defects per addressed line.


The role of electronegativity on the extent of nitridation of group 5 metals as revealed by reactions of tantalum cluster cations with ammonia molecules.
Reactions of the free tantalum cation, Ta+, and tantalum cluster cations, Tan+ (n = 2-10), with ammonia are presented. The reaction of the monomer cation, Ta+, with two molecules of NH3 leads to the formation of TaN2H2+ along with release of two H2 molecules. The dehydrogenation occurs until the formal oxidation number of the tantalum atom reaches +5. On the other hand, all the tantalum cluster cations, Tan+, react with two molecules of NH3 and form TanN2+ with the release of three H2 molecules. Further exposure to ammonia showed that TanNmH+ and TanNm+ are produced through successive reactions; a pure nitride and three H2 molecules are formed for every other NH3 molecule. The nitridation occurred until the formal oxidation number of the tantalum atoms reaches +5 as in the case of TaN2H2+ in contrast to other group 5 elements, i.e., vanadium and niobium, which have been reported to produce nitrides with lower oxidation states. The present results on small gas-phase metal-nitride clusters show correlation with their bulk properties: tantalum is known to form bulk nitrides in the oxidation states of either +5 (Ta3N5) or +3 (TaN), whereas vanadium and niobium form nitrides in the oxidation state of +3 (VN and NbN). Along with DFT calculations, these findings reveal that nitridation is driven by the electron-donating ability of group 5 elements, i.e., electronegativity of the metal plays a key role in determining the composition of the metal nitrides.


[HEMOGLOBIN A1c AND THE QUALITY OF DIABETES CARE].
Global diabetes epidemics is currently representing one of the most prominent medical and societal challenges. Hemoglobin A1c (HbA1c), a biochemical marker of an average blood glucose concentration has been used for more than 30 years as a clinical indicator of both diabetes treatment efficacy and the risk for development of complications. Recently, HbA1C was proposed as a diabetes diagnostic test as well. Regular monitoring of glycemic control and adjustment of therapy towards the recommended HbA1c-based treatment-goals is a pivotal request of contemporary diabetes care guidelines, as well as a quality indicator proclaimed by numerous national health-care-delivery systems. Standardized and attainable analytical methodology of high-quality and a good knowledge on determinants of biological variability, able to influence test results, are crucial elements for the confident clinical use of HbA1c. In this review, essential analytical and clinical aspects necessary for the reliable use of HbA1c results in diabetes care are concisely presented, together with the degree of Croatian laboratory and clinical practice harmonization with the relevant international standards.


Sinonasal microbiome sampling: a comparison of techniques.
The role of the sino-nasal microbiome in CRS remains unclear. We hypothesized that the bacteria within mucosal-associated biofilms may be different from the more superficial-lying, free-floating bacteria in the sinuses and that this may impact on the microbiome results obtained. This study investigates whether there is a significant difference in the microbiota of a sinonasal mucosal tissue sample versus a swab sample. Cross-sectional study with paired design. Mucosal biopsy and swab samples were obtained intra-operatively from the ethmoid sinuses of 6 patients with CRS. Extracted DNA was sequenced on a Roche-454 sequencer using 16S-rRNA gene targeted primers. Data were analyzed using QIIME 1.8 software package. At a maximum subsampling depth of 1,100 reads, the mean observed species richness was 33.3 species (30.6 for swab, versus 36 for mucosa; p > 0.05). There was no significant difference in phylogenetic and non-phylogenetic alpha diversity metrics (Faith's PD_Whole_Tree and Shannon's index) between the two sampling methods (p > 0.05). The type of sample also had no significant effect on phylogenetic and non-phylogenetic beta diversity metrics (Unifrac and Bray-Curtis; p > 0.05). We observed no significant difference between the microbiota of mucosal tissue and swab samples. This suggests that less invasive swab samples are representative of the sinonasal mucosa microbiome and can be used for future sinonasal microbiome studies.


Association between SARS-CoV-2 Seroprevalence in Nursing Home Staff and Resident COVID-19 Cases and Mortality: A Cross-Sectional Study.
The burden of COVID-19 has disproportionately impacted the elderly, who are at increased risk of severe disease, hospitalization, and death. This cross-sectional study aimed to assess the association between SARS-CoV-2 seroprevalence among nursing home staff, and cumulative incidence rates of COVID-19 cases, hospitalizations, and deaths among residents. Staff seroprevalence was estimated within the SEROCoV-WORK+ study between May and September 2020 across 29 nursing homes in Geneva, Switzerland. Data on nursing home residents were obtained from the canton of Geneva for the period between March and August 2020. Associations were assessed using Spearman's correlation coefficient and quasi-Poisson regression models. Overall, seroprevalence among staff ranged between 0 and 31.4%, with a median of 8.3%. A positive association was found between staff seroprevalence and resident cumulative incidence of COVID-19 cases (correlation coefficient R = 0.72, 95%CI 0.45-0.87; incidence rate ratio [IRR] = 1.10, 95%CI 1.07-1.17), hospitalizations (R = 0.59, 95%CI 0.25-0.80; IRR = 1.09, 95%CI 1.05-1.13), and deaths (R = 0.71, 95%CI 0.44-0.86; IRR = 1.12, 95%CI 1.07-1.18). Our results suggest that SARS-CoV-2 transmission between staff and residents may contribute to the spread of the virus within nursing homes. Awareness among nursing home professionals of their likely role in the spread of SARS-CoV-2 has the potential to increase vaccination coverage and prevent unnecessary deaths due to COVID-19.


Hibernation temperature-dependent Pseudogymnoascus destructans infection intensity in Palearctic bats.
White-nose syndrome (WNS) is a fungal disease caused by Pseudogymnoascus destructans that is devastating to Nearctic bat populations but tolerated by Palearctic bats. Temperature is a factor known to be important for fungal growth and bat choice of hibernation. Here we investigated the effect of temperature on the pathogenic fungal growth in the wild across the Palearctic. We modelled body surface temperature of bats with respect to fungal infection intensity and disease severity and were able to relate this to the mean annual surface temperature at the site. Bats that hibernated at lower temperatures had less fungal growth and fewer skin lesions on their wings. Contrary to expectation derived from laboratory P. destructans culture experiments, natural infection intensity peaked between 5 and 6°C and decreased at warmer hibernating temperature. We made predictive maps based on bat species distributions, temperature and infection intensity and disease severity data to determine not only where P. destructans will be found but also where the infection will be invasive to bats across the Palearctic. Together these data highlight the mechanistic model of the interplay between environmental and biological factors, which determine progression in a wildlife disease.


Long-term survival of infants with atrioventricular septal defects.
To examine the variation in survival in infants with atrioventricular septal defects (AVSD) with demographic factors and clinical characteristics, including the presence of Down syndrome. We selected infants with all types of AVSD with Down syndrome (n = 177) and without Down syndrome (n = 161), born between Jan 1, 1979, and Dec 31, 2003 and identified through the Metropolitan Atlanta Congenital Defects Program (MACDP). Infants were classified by the complexity of their cardiac defects and presence of major non-cardiac malformations. Deaths (n = 111) were identified through 2004 with linkage with state vital records and the National Death Index. Kaplan-Meier survival probabilities and adjusted hazard ratios (HRs) were calculated in relation to demographic and clinical characteristics. Children with AVSD and Down syndrome had a similar overall survival probability (70%) as those without Down syndrome (69%). Mortality was higher in children with a complex AVSD (adjusted HR = 7.0; 95% CI, 3.1-15.5) and in children with > or =2 major non-cardiac malformations (adjusted HR = 3.4; 95% CI, 1.8-6.5) and was lower in children in the 1992 to 2003 birth cohort (adjusted HR = 0.6; 95% CI, 0.4-0.998). Down syndrome was not a prognostic factor. Our findings might be helpful in assessing the long-term prognosis of infants with AVSD.


The place of renin in the mechanism of hypertension in chronic renal disease.
The history of the development of ideas on the cause of renal hypertension is first discussed. Growth of knowledge of renin and angiotensin from 1898 to the present is shown to depend upon better and more specific assays for each part of the system, which has enabled knowledge of the role of the renin-angiotensin system in various forms of hypertension to be assessed accurately. The difficulties of assessing varying levels in relation to their biological effect is stressed and the importance of the use of blockers of both renin and angiotensin is shown to mark a very large advance in the study of various forms of renal hypertension where there is a complicated relationship, still ill-defined, between renin, angiotensin, sodium and body fluid volumes.


Impulsivity moderates the effect of approach bias modification on healthy food consumption.
The study aimed to modify approach bias for healthy and unhealthy food and to determine its effect on subsequent food consumption. In addition, we investigated the potential moderating role of impulsivity in the effect of approach bias re-training on food consumption. Participants were 200 undergraduate women (17-26 years) who were randomly allocated to one of five conditions of an approach-avoidance task varying in the training of an approach bias for healthy food, unhealthy food, and non-food cues in a single session of 10 min. Outcome variables were approach bias for healthy and unhealthy food and the proportion of healthy relative to unhealthy snack food consumed. As predicted, approach bias for healthy food significantly increased in the 'avoid unhealthy food/approach healthy food' condition. Importantly, the effect of training on snack consumption was moderated by trait impulsivity. Participants high in impulsivity consumed a greater proportion of healthy snack food following the 'avoid unhealthy food/approach healthy food' training. This finding supports the suggestion that automatic processing of appetitive cues has a greater influence on consumption behaviour in individuals with poor self-regulatory control.


Dissecting the phenotypic components of crop plant growth and drought responses based on high-throughput image analysis.
Significantly improved crop varieties are urgently needed to feed the rapidly growing human population under changing climates. While genome sequence information and excellent genomic tools are in place for major crop species, the systematic quantification of phenotypic traits or components thereof in a high-throughput fashion remains an enormous challenge. In order to help bridge the genotype to phenotype gap, we developed a comprehensive framework for high-throughput phenotype data analysis in plants, which enables the extraction of an extensive list of phenotypic traits from nondestructive plant imaging over time. As a proof of concept, we investigated the phenotypic components of the drought responses of 18 different barley (Hordeum vulgare) cultivars during vegetative growth. We analyzed dynamic properties of trait expression over growth time based on 54 representative phenotypic features. The data are highly valuable to understand plant development and to further quantify growth and crop performance features. We tested various growth models to predict plant biomass accumulation and identified several relevant parameters that support biological interpretation of plant growth and stress tolerance. These image-based traits and model-derived parameters are promising for subsequent genetic mapping to uncover the genetic basis of complex agronomic traits. Taken together, we anticipate that the analytical framework and analysis results presented here will be useful to advance our views of phenotypic trait components underlying plant development and their responses to environmental cues.


Obesity, Angiotensin-Blocking Drugs, and Acute Kidney Injury in Orthopedic Surgery.
Postoperative acute kidney injury occurs in 7% to 11% of orthopedic surgeries. The effect of preoperative angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the development of postoperative acute kidney injury remains controversial. Adipose tissue has its own independently regulated angiotensin system. The primary aim of this study was to examine the effects of obesity and preoperative ACEIs and ARBs on postoperative acute kidney injury. Charts were reviewed of adult elective orthopedic surgery patients during a 2-year period when patients were instructed to take their ACEI or ARB on the morning of surgery. The patients were divided into an obese cohort (body mass index [BMI] ≥30 kg/m2) and a nonobese cohort (BMI <30 kg/m2). A multivariable model was created for the outcome of acute kidney injury, using obesity as a primary predictor and adjusting for demographics, medications, comorbidities, and intraoperative parameters in a logistic regression analysis. Obesity increased the likelihood of developing acute kidney injury after orthopedic surgery (odds ratio [OR], 1.86; 95% CI, 1.07-3.22; P=.028). For every 5-unit increase in BMI, the odds of acute kidney injury were 1.43 (95% CI, 1.26-1.62; P<.001). When receiving ACEIs or ARBs, only the nonobese patients had a statistically increased likelihood of postoperative acute kidney injury (OR, 3.30; 95% CI, 1.12-9.70; P=.030). Obesity is an independent risk factor for postoperative acute kidney injury. Obesity appears to influence the effect that preoperative ACEIs and ARBs have on postoperative acute kidney injury. [Orthopedics. 2021;44(2):e253-e258.].


Exploring the theranostic potentials of miRNA and epigenetic networks in autoimmune diseases: A comprehensive review.
Autoimmune diseases (AD) are severe pathophysiological ailments that are stimulated by an exaggerated immunogenic response towards self-antigens, which can cause systemic or site-specific organ damage. An array of complex genetic and epigenetic facets majorly contributes to the progression of AD, thus providing significant insight into the regulatory mechanism of microRNA (miRNA). miRNAs are short, non-coding RNAs that have been identified as essential contributors to the post-transcriptional regulation of host genome expression and as crucial regulators of a myriad of biological processes such as immune homeostasis, T helper cell differentiation, central and peripheral tolerance, and immune cell development. This article tends to deliberate and conceptualize the brief pathogenesis and pertinent epigenetic regulatory mechanism as well as miRNA networks majorly affecting five different ADs namely rheumatoid arthritis (RA), type 1 diabetes, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disorder (IBD) thereby providing novel miRNA-based theranostic interventions. Pertaining to the differential expression of miRNA attributed in target tissues and cellular bodies of innate and adaptive immunity, a paradigm of scientific expeditions suggests an optimistic correlation between immunogenic dysfunction and miRNA alterations. Therefore, it is not astonishing that dysregulations in miRNA expression patterns are now recognized in a wide spectrum of disorders, establishing themselves as potential biomarkers and therapeutic targets. Owing to its theranostic potencies, miRNA targets have been widely utilized in the development of biosensors and other therapeutic molecules originating from the same.


Characterization of androgen receptor structure and nucleocytoplasmic shuttling of the rice field eel.
Androgen receptor (AR) plays a critical role in prostate cancer and male sexual differentiation. We have identified AR from a primitive vertebrate with a sex reversal characteristic, the rice field eel. AR of this species (eAR) is distinct from human AR, especially in the ligand binding domain (LBD), and its expression in gonads shows an increasing tendency during gonadal transformation from ovary via ovotestis to testis. eAR has a restricted androgen-dependent transactivation function after a nuclear translocation upon dihydrotestosterone exposure. A functional nuclear localization signal was further identified in the DNA binding domain and hinge region. Although nuclear export is CRM1-independent, eAR has a novel nuclear export signal, which is negatively charged, indicating that a nuclear export pathway may be mediated by electrostatic interaction. Further, our studies have identified critical sequences for ligand binding in the C terminus. A structure of three α-helices in the LBD has been conserved from eels to humans during vertebrate evolution, despite a distinct amino acid sequence. Mutation analysis confirmed that the LBD is essential for dihydrotestosterone-induced nuclear import of eAR and following transactivation function in the nucleus. In addition, eAR interacts with both Sox9a1 and Sox9a2, and their interaction regulates transactivation of eAR. Our data suggest that the primitive species conserves and especially acquires key novel domains, the nuclear export signal and LBD, for the eAR function in spite of a rapid sequence evolution.


Bortezomib, a proteasome inhibitor, attenuates angiotensin II-induced hypertension and aortic remodeling in rats.
Hypertension is a highly prevalent disorder and a major risk factor for cardiovascular diseases. Hypertensive vascular remodeling is the pathological mal-adaption of blood vessels to the hypertensive condition that contributes to further development of high blood pressure and end-organ damage. Hypertensive remodeling involves, at least in part, changes in protein turnover. The ubiquitin proteasome system (UPS) is a major protein quality and quantity control system. This study tested the hypothesis that the proteasome inhibitor, bortezomib, would attenuate AngII-induced hypertension and its sequelae such as aortic remodeling in rats. Male Sprague Dawley rats were subjected to AngII infusion for two weeks in the absence or presence of bortezomib. Mean arterial pressure was measured in conscious rats. Aortic tissue was collected for estimation of wall area, collagen deposition and expression of tissue inhibitors of matrix metalloproteases (TIMP), Ki67 (a marker of proliferation), reactive oxygen species (ROS) and VCAM-1 (a marker of inflammation). AngII infusion increased arterial pressure significantly (160±4 mmHg vs. vehicle treatment 133±2 mmHg). This hypertensive response was attenuated by bortezomib (138±5 mmHg). AngII hypertension was associated with significant increases in aortic wall to lumen ratio (∼29%), collagen deposition (∼14%) and expression of TIMP1 and TIMP2. AngII also increased MMP2 activity, proteasomal chymotrypsin-like activity, Ki67 staining, ROS generation and VCAM-1 immunoreactivity. Co-treatment of AngII-infused rats with bortezomib attenuated these AngII-induced responses. Collectively, these data support the idea that proteasome activity contributes to AngII-induced hypertension and hypertensive aortic vascular remodeling at least in part by modulating TIMP1/2 and MMP2 function. Preliminary observations are consistent with a role for ROS, inflammatory and proliferative mechanisms in this effect. Further understanding of the mechanisms by which the proteasome is involved in hypertension and vascular structural remodeling may reveal novel targets for pharmacological treatment of hypertension, hypertensive remodeling or both.


Evidence that glucose increases monocyte binding to human aortic endothelial cells.
The rate of atherosclerosis is accelerated in humans with diabetes. The adhesion of monocytes to the vascular endothelium is a key event in the development of atherosclerosis. Alloxan (ALX)-induced diabetes in rabbits causes leukocyte accumulation on the arterial surface. However, the effect of glucose exposure on monocyte binding is not understood. We evaluated the effect of chronic elevated glucose on human monocyte binding to human aortic endothelial cells (HAEC) in culture. Monocyte binding to HAEC was significantly increased by chronic incubation of HAEC in high glucose for 7-10 days (CH-HG; 25 mM) compared with cells cultured for the same time in normal glucose (5.5 mM; CH-HG, 188 +/- 10 cells/field vs. normal glucose, 111 +/- 7; P < 0.0005). Use of mannitol at a concentration to stimulate the hyperosmolar effects of glucose did not significantly alter monocyte binding. Acute 20-min exposure of HAEC to high glucose did not alter monocyte binding. The adherence of HL-60 cells, a neutrophil-like cell line, or human neutrophils was not induced by CH-HG culture. High glucose-induced monocyte binding was not associated with induction of the major endothelial cell adhesion molecules, including E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 (ICAM-1). A monoclonal antibody TS1-18 to the beta 2 integrin component that is involved in binding to ICAM-1 on endothelial cells significantly reduced monocyte binding, whereas anti-VLA-4 antibody was not effective. These results suggest that hyperglycemia can accelerate the rate of atherosclerosis in diabetics by increasing monocyte binding to the endothelium.


How does spa treatment affect cardiovascular function and vascular endothelium in patients with generalized osteoarthritis? A pilot study through plasma asymmetric di-methyl arginine (ADMA) and L-arginine/ADMA ratio.
The study aims to investigate the effect of spa treatment on vascular endothelium and clinical symptoms of generalized osteoarthritis. Forty generalized osteoarthritis (GOA) patients referred to a government spa hospital, and 40 GOA patients followed on university hospital locomotor system disease ambulatory clinics were included as study and control groups, respectively. Study group received spa treatment including thermal water baths, physical therapy modalities, and exercises. Control group was followed with home exercises for 15 days. Plasma ADMA, L-arginine, L-arginine/ADMA ratio, routine blood analyses, 6-min walking test, including fingertip O2 saturation, systolic/diastolic blood pressure, and pulse rate, were measured at the beginning and at the end of treatment. Groups were evaluated with VAS pain, patient, and physician global assessment; HAQ; and WOMAC at the beginning, at the end, and after 1 month of treatment. In study group, L-arginine and L-arginine/ADMA ratio showed statistically significant increase after treatment. Plasma ADMA levels did not change. There is no significant difference in intergroup comparison. Study group displayed statistically significant improvements in all clinical parameters. The study showed that spa treatment does not cause any harm to the vascular endothelium through ADMA. Significant increase in plasma L-arginine and L-arginine/ADMA ratio suggests that balneotherapy may play a preventive role on cardiovascular diseases. Balneotherapy provides meaningful improvements on clinical parameters of GOA.


Sequence and magnitude of ventricular volume changes in painful and painless myocardial ischemia.
Stimulation of left ventricular stretch receptors has been proposed as a possible mechanism for the occurrence of cardiac pain. Changes in left ventricular volume were continuously assessed in 12 patients during 11 spontaneous (two painful) and 12 ergometrine-induced (nine painful) ischemic attacks with a precordial scintillation probe and blood pool labeling with technetium-99m. In all ischemic episodes, spontaneous or induced, painful or painless, severe dilatation of the left ventricle was consistently observed. These changes always preceded the onset of ST segment shifts and occurred long before pain, when present. The maximum increase in end-diastolic volume was slightly greater in painful than in painless episodes, 38 +/- 8.0% versus 28 +/- 12.4%, but no significant difference was observed in the rate of volume change or in the maximum increase of end-systolic volume (133 +/- 50% and 110 +/- 27.3%), stroke volume (-28 +/- 15% and -25 +/- 12.4%), or ejection fraction (-32 +/- 8.7% and -26 +/- 6.0%). Although the maximum end-diastolic volume achieved is greater in painful episodes, this effect cannot be separated from that of duration, and, furthermore, there was no significant difference in end-diastolic volume at the moment chest pain began. Thus, in patients with angina at rest, transient asymptomatic ST segment shifts are consistently associated with large changes in left ventricular volume, similar to those observed during painful episodes. The rate and extent of acute left ventricular dilatation do not appear to be factors directly causing anginal pain.


Commercial pressures and professional ethics: troubling revisions to the recent ACOG Practice Bulletins on surgery for pelvic organ prolapse.
Commercial interests are reshaping the practice of gynecological surgery by promoting the use of trochar-and-mesh surgical "kits" for the treatment of stress incontinence and pelvic organ prolapse. In this article, we discuss the ethical implications of changes in surgical practice that are driven by commercial interests. We point out the dangers inherent in the adoption of new procedures without adequate and documented evidence to support their safety and efficacy. We discuss the most recent American College of Obstetricians and Gynecologists (ACOG) Practice Bulletins on pelvic organ prolapse (numbers 79 and 85) which were altered without explanation to downplay the experimental nature of these commercial products. We suggest that in so doing, ACOG is not meeting its fiduciary responsibilities to patients and is undermining important professional values.


The prognostic value of right ventricular deformation derived from cardiac magnetic resonance tissue tracking for all-cause mortality in light-chain amyloidosis patients.
Early detection of right ventricular (RV) dysfunction is vital for determining the prognosis of light-chain amyloidosis (AL) patients. While few studies focused on RV deformation due to the limitation of research methods. The aim of this study was to determine the prognostic significance of RV myocardial strain in AL patients assessed by cardiac magnetic resonance (CMR) tissue tracking. Sixty-four AL patients (28 females and 36 males, mean age 58±12.8 years old; range 25-81 years old) were enrolled from 1 October 2014 through 31 March 2017 and compared with 20 age- and sex-matched controls. Fifty-one AL patients met the criteria for cardiac amyloidosis (CA). Deformation parameters of both RV and left ventricle (LV) were measured by the CMR tissue tracking technique including myocardial global radial peak strain (GRPS), global circumferential peak strain (GCPS), and global longitudinal peak strain (GLPS). The follow-up time was 20 months or until the occurrence of death. Thirty-two (50%) had preserved RV ejection fraction (RVEF ≥45%). AL patients had significantly lower RV-GRPS (20.3±2.12 vs. 31.31±7.61), GCPS (-2.12±0.88 vs. -13.71±2.53), and GLPS (-5.33±0.64 vs. -14.239±2.99) than controls even RVEF remain preserved (all P<0.001). Compared with controls and patients without CA, RV-GRPS (12.26±1.26 vs. 29.72±3.54, P<0.001) and RV-GLPS (-3.78±2.25 vs. -5.66±2.08, P<0.05) were significantly lower in patients with CA. Cox multivariate analyses demonstrated that RV-GRPS [hazard ratio (HR) =0.93, 95% CI: 0.88-0.98, P=0.007] and Mayo stage were (HR =3.11, 95% CI: 1.30-7.41, P=0.01) predictors of mortality in AL patients. CMR tissue tracking is a feasible and highly reproducible technique for the analysis of RV deformation and could aid in the early diagnosis of RV involvement in AL patients. RV-GRPS of RV strain and Mayo stage provides prognostic information about mortality in AL patients.


Recent advances in stem cell neurobiology.
1. Neural stem cells can be cultured from the CNS of different mammalian species at many stages of development. They have an extensive capacity for self-renewal and will proliferate ex vivo in response to mitogenic growth factors or following genetic modification with immortalising oncogenes. Neural stem cells are multipotent since their differentiating progeny will give rise to the principal cellular phenotypes comprising the mature CNS: neurons, astrocytes and oligodendrocytes. 2. Neural stem cells can also be derived from more primitive embryonic stem (ES) cells cultured from the blastocyst. ES cells are considered to be pluripotent since they can give rise to the full cellular spectrum and will, therefore, contribute to all three of the embryonic germ layers: endoderm, mesoderm and ectoderm. However, pluripotent cells have also been derived from germ cells and teratocarcinomas (embryonal carcinomas) and their progeny may also give rise to the multiple cellular phenotypes contributing to the CNS. In a recent development, ES cells have also been isolated and grown from human blastocysts, thus raising the possibility of growing autologous stem cells when combined with nuclear transfer technology. 3. There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS, and thereby raising the possibility of promoting endogenous neural reconstruction. 4. Such reports have fuelled expectations for the clinical exploitation of neural stem cells in cell replacement or recruitment strategies for the treatment of a variety of human neurological conditions including Parkinson's disease (PD), Huntington's disease, multiple sclerosis and ischaemic brain injury. Owing to their migratory capacity within the CNS, neural stem cells may also find potential clinical application as cellular vectors for widespread gene delivery and the expression of therapeutic proteins. In this regard, they may be eminently suitable for the correction of genetically-determined CNS disorders and in the management of certain tumors responsive to cytokines. Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies. 5. While considerable recent progress has been made in terms of developing new techniques allowing for the long-term culture of human stem cells, the successful clinical application of these cells is presently limited by our understanding of both (i) the intrinsic and extrinsic regulators of stem cell proliferation and (ii) those factors controlling cell lineage determination and differentiation. Although such cells may also provide accessible model systems for studying neural development, progress in the field has been further limited by the lack of suitable markers needed for the identification and selection of cells within proliferating heterogeneous populations of precursor cells. There is a further need to distinguish between the committed fate (defined during normal development) and the potential specification (implying flexibility of fate through manipulation of its environment) of stem cells undergoing differentiation. 6. With these challenges lying ahead, it is the opinion of the authors that stem-cell therapy is likely to remain within the experimental arena for the foreseeable future. In this regard, few (if any) of the in vivo studies employing neural stem cell grafts have shown convincingly that behavioural recovery can be achieved in the various model paradigms. Moreover, issues relating to the quality control of cultured cells and their safety following transplantation have only begun to be addressed. 7. While on the one hand cell biotechnologists have been quick to realise the potential commercial value, human stem cell research and its clinical applications has been the subject of intense ethical and legislative considerations. The present chapter aims to review some recent aspects of stem cell research applicable to developmental neurobiology and the potential applications in clinical neuroscience.


Powdered diatrizoic acid for radiography of the respiratory tract. Part I. Experimental investigation.
Powdered diatrizoic acid as a contrast medium administered by inhalation and insufflation for visualization of the airways was tested in vitro and in 21 dogs. Good radiopacity of the contrast medium and its antibacterial activity was found in vitro. In the majority of animal experiments visualization of the bronchial tree down to segmental and partially to subsegmental bronchi with only minimal agglomeration of contrast medium and with good or very good demonstration of anatomic details was achieved. In the majority of dogs contrast medium was eliminated from the lungs within 18 hours. Arterial blood gases tested on 5 dogs showed only unimportant changes after contrast medium administration. No adverse reactions were observed. Histologic and ultrastructural examinations after contrast studies showed phagocytic reaction to diatrizoic acid, transient impairment of production of surfactant, reactive changes of bronchial mucosa, and no fibrotic changes in the long-term observation.


Cancer, a disease of aging (part 1) - trends in older adult cancer mortality in Switzerland 1991-2008.
It is crucial for aging societies to evaluate trends in cancer mortality rates of older adults. This study examined socio-demographic and regional characteristics specifically focused on the cancer mortality experience of older adults in Switzerland. This study included all individuals ≥65 years based on 1990/2000 censuses linked to mortality records to end of 2008 in the Swiss National Cohort. Gender-age-specific (<65, 65-74, 75-84, 85+ years) mortality rates were calculated as observed (cancer deaths/person years) and expected from Poisson models adjusted for changes in death record coding over follow-up. Cancer mortality, except for lung cancer, increased with advancing age. Older men in all age groups had overall higher cancer mortality rates than older women and showed a consistent decline in all-cancer mortality (age 65-74 years 1991 rate ratio (RR) = 1.13 [95%CI 1.08, 1.19]; 2008 RR = 0.88 [95%CI 0.86, 0.90], compared to rates 2000). In contrast, older women in all age groups showed early declines with a levelling-off of all-cancer mortality beginning in 2000 (age 65-74 years 1991 RR = 1.20 [95%CI 1.14, 1.27]; 2008 RR = 0.96 [95%CI 0.93, 0.98], compared to rates 2000). For older men there appeared to be an education effect for all-cancer and lung cancer mortality; highest rates in older men with compulsory education. Younger old women living alone or in suburban areas had the most sharpest increase in lung cancer mortality rates. This comprehensive epidemiological analysis of cancer mortality trends in older adults provides further evidence that in Switzerland (like other developed countries) cancer is a disease of aging with important gender-age-specific variations representing major public health challenges for aging societies.


Determination of transmural location of onset of activation from cardiac surface electrograms.
Methods of estimating depth of origin of ventricular activation from cardiac surface electrograms were evaluated in experiments on eight dogs. The ventricles were paced via multielectrode needle arrays placed transmurally in from four to six locations in the wall of the left ventricle. A multiplexed data-recording system was used to simultaneously record from 64 unipolar cardiac surface electrodes during pacing at each multielectrode needle site. The four indexes evaluated were the maximum and average gradients of activation isochrones around the site of earliest epicardial activation, the QRS area at the site of earliest epicardial activation, the interval between the QRS onset computed from all 64 epicardial surface electrograms, and the time of the minimum dV/dt in the electrogram displaying the earliest epicardial activation time (t(ee)-t(rmso) interval). Correlation coefficients between depth of stimulation and average and maximum gradients of isochrones, QRS area at the site of earliest epicardial activation, and t(ee)-t(rmso) interval were 0.985 or higher. These methods, particularly those involving gradients of isochrones, should be useful for evaluating electromaps of patients undergoing surgery for ablation of tachyarrhythmias.


Alternative complement pathway deregulation is correlated with dengue severity.
The complement system, a key component that links the innate and adaptive immune responses, has three pathways: the classical, lectin, and alternative pathways. In the present study, we have analyzed the levels of various complement components in blood samples from dengue fever (DF) and dengue hemorrhagic fever (DHF) patients and found that the level of complement activation is associated with disease severity. Patients with DHF had lower levels of complement factor 3 (C3; p = 0.002) and increased levels of C3a, C4a and C5a (p<0.0001) when compared to those with the less severe form, DF. There were no significant differences between DF and DHF patients in the levels of C1q, immunocomplexes (CIC-CIq) and CRP. However, small but statistically significant differences were detected in the levels of MBL. In contrast, the levels of two regulatory proteins of the alternative pathway varied widely between DF and DHF patients: DHF patients had higher levels of factor D (p = 0.01), which cleaves factor B to yield the active (C3bBb) C3 convertase, and lower levels of factor H (p = 0.03), which inactivates the (C3bBb) C3 convertase, than did DF patients. When we considered the levels of factors D and H together as an indicator of (C3bBb) C3 convertase regulation, we found that the plasma levels of these regulatory proteins in DHF patients favored the formation of the (C3bBb) C3 convertase, whereas its formation was inhibited in DF patients (p<0.0001). The data suggest that an imbalance in the levels of regulatory factors D and H is associated with an abnormal regulation of complement activity in DHF patients.


Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults.
Epidemiologic studies have found whole-grain intake to be inversely associated with the risk of type 2 diabetes and heart disease. We tested the hypothesis that whole-grain consumption improves insulin sensitivity in overweight and obese adults. This controlled experiment compared insulin sensitivity between diets (55% carbohydrate, 30% fat) including 6-10 servings/d of breakfast cereal, bread, rice, pasta, muffins, cookies, and snacks of either whole or refined grains. Total energy needs were estimated to maintain body weight. Eleven overweight or obese [body mass index (in kg/m(2)): 27-36] hyperinsulinemic adults aged 25-56 y participated in a randomized crossover design. At the end of each 6-wk diet period, the subjects consumed 355 mL (12 oz) of a liquid mixed meal, and blood samples were taken over 2 h. The next day a euglycemic hyperinsulinemic clamp test was administered. Fasting insulin was 10% lower during consumption of the whole-grain than during consumption of the refined-grain diet (mean difference: -15 +/- 5.5 pmol/L; P = 0.03). After the whole-grain diet, the area under the 2-h insulin curve tended to be lower (-8832 pmol.min/L; 95% CI: -18720, 1062) than after the refined-grain diet. The rate of glucose infusion during the final 30 min of the clamp test was higher after the whole-grain diet (0.07 x 10(-4) mmol.kg(-1).min(-1) per pmol/L; 95% CI: 0.003 x 10(-4), 0.144 x 10(-4)). Insulin sensitivity may be an important mechanism whereby whole-grain foods reduce the risk of type 2 diabetes and heart disease.


Molecular structures of citrate and tricarballylate adsorbed on alpha-FeOOH particles in aqueous suspensions.
In this work, the adsorption of citric (2-hydroxypropane-1,2,3-tricarboxylic acid) and tricarballylic (propane-1,2,3-tricarboxylic acid) acids onto alpha-FeOOH (goethite) in aqueous suspensions was studied as a function of pH and total ligand concentration in 0.1 M NaCl at 25.0 degrees C, and the molecular structures of the surface complexes formed were analyzed by means of ATR-FTIR spectroscopy. The adsorption experiments were carried out as a series of batch experiments, and a newly developed simultaneous infrared and potentiometric titration technique was used to collect in situ infrared spectra with high signal-to-noise ratios. The high quality of the infrared spectra allowed analysis by means of two-dimensional correlation spectroscopy formalism that aided the resolution of pH-dependent spectral features. This has enabled the detection of two previously unidentified citrate-goethite surface complexes: one protonated species at low pH, and one inner sphere complex prevailing at high pH and coordinated via a combination of hydroxyl and carboxylate groups. In addition, an inner sphere complex involving only carboxylate coordination predominating at low pH and an outer sphere complex existing in the circumneutral pH region were identified. The behavior of tricarballylate parallels that of citrate, except no inner sphere surface complex is formed at high pH values, which is in accordance with the lack of an alpha-hydroxyl group. The comparison between citrate and tricarballylate reinforces previous observations showing that inner sphere surface complexes of pure carboxylates at water-iron oxide interfaces are suppressed at high pH values, where outer sphere species are relatively more predominant. It also shows that significant amounts of inner sphere surface complexes of carboxylates only seem to form in the basic pH region when the ligands contain complementary functional groups, such as the hydroxyl or amine groups.


Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Cefiderocol, and Novel Darobactin Analogs against Multidrug-Resistant Pseudomonas aeruginosa Isolates from Pediatric and Adolescent Cystic Fibrosis Patients.
The emergence and spread of antimicrobial resistance (AMR) in Gram-negative pathogens, such as carbapenem-resistant Pseudomonas aeruginosa, pose an increasing threat to health care. Patients with immunodeficiencies or chronic pulmonary disease, like cystic fibrosis (CF), are particularly vulnerable to Pseudomonas infections and depend heavily on antibiotic therapy. To broaden limited treatment options, this study evaluated the potency of the recently licensed drugs ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), and cefiderocol (FDC) as well as two novel preclinical antibiotics, darobactins B (DAR B) and B9 (DAR B9), against clinical P. aeruginosa isolates derived from respiratory samples of CF patients. We observed high levels of resistance to all three newly licensed drugs, with cefiderocol exhibiting the best activity. From the 66 investigated P. aeruginosa isolates, a total of 53% were resistant to CZA, 49% to C/T, and 30% to FDC. Strikingly, 52 of the evaluated isolates were obtained from CF patients prior to market introduction of the drugs. Thus, our results suggest that resistance to CZA, C/T, and FDC may be due to preexisting resistance mechanisms. On the other hand, our two novel preclinical compounds performed better than (CZA and C/T) or close to (FDC) the licensed drugs-most likely due to the novel mode of action. Thus, our results highlight the necessity of global consistency in the area of antibiotic stewardship to prevent AMR from further impairing the potency of antibiotics in clinical practice. Ultimately, this study demonstrates the urgency to support the development of novel antimicrobials, preferably with a new mode of action such as darobactins B and B9, two very promising antimicrobial compounds for the treatment of critically ill patients suffering from multidrug-resistant Gram-negative (MRGN) infections. IMPORTANCE Antimicrobial resistance (AMR) represents an ever increasing threat to the health care system. Even recently licensed drugs are often not efficient for the treatment of infections caused by Gram-negative bacteria, like Pseudomonas aeruginosa, a causative agent of lung infections. To address this unmet medical need, innovative antibiotics, which possess a new mode of action, need to be developed. Here, the antibiogram of clinical isolates derived from cystic fibrosis patients was generated and new bicyclic heptapeptides, which inhibit the outer membrane protein BamA, exhibited strong activity, also against multidrug-resistant isolates.


Therapeutic Considerations for Antihyperglycemic Agents in Diabetic Kidney Disease.
Diabetic kidney disease is among the most frequent complications of diabetes, with approximately 50% of patients with ESRD attributed to diabetes in developed countries. Although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced GFR in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the cardiovascular and renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and sodium-glucose cotransporter 2 inhibitor classes of medications. Ongoing studies will continue to inform future use of these agents in patients with diabetic kidney disease.


Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival.
Vitamin D metabolites, immunologic, virologic, and clinical parameters, and survival time were determined in 22 asymptomatic human immunodeficiency virus (HIV)-infected patients (CDC stage II/III), 31 symptomatic HIV-infected patients (CDC stage IV), and 28 HIV-seronegative controls. Significantly lower serum levels of 1,25-vitamin D (1,25D) were found in symptomatic patients (median, 34 pg/mL; 25th-75th percentile, 21-45) compared with controls (49 pg/mL; 39-59) and asymptomatic patients (45 pg/mL; 42-50). In HIV-infected subjects, the serum level of 1,25D was positively correlated with CD4+ cell counts in peripheral blood (r = .35, P < .05) and negatively correlated with the level of serum neopterin (r = -.36, P < .01). HIV-infected patients with abnormally low 1,25D (< 25 pg/mL) also had shorter survival times than other HIV-infected subjects (P < .01). Low 1,25D levels did not appear to be related to vitamin D deficiency.


Cytoplasm-localized SIRT1 enhances apoptosis.
In general, SIRT1 is localized in nuclei. Here, we showed that endogenous and exogenous SIRT1 were both able to partially localize in cytoplasm in certain cell lines, and cytoplasm-localized SIRT1 was associated with apoptosis and led to increased sensitivity to apoptosis. Furthermore, we demonstrated that translocation of nucleus-localized SIRT1 from nuclei to cytoplasm was the main pathway leading to localization of SIRT1 in cytoplasm. In HeLa cells, wild type SIRT1 was completely localized in nuclei. By truncation of two predicted nuclear localization signals or fusion with an exogenous nuclear export signal, SIRT1 was partially localized in cytoplasm of HeLa cells and resulted in increased sensitivity to apoptosis. The apoptosis enhanced by cytoplasm-localized SIRT1 was independent of its deacetylase activity, but dependent on caspases. SIRT1 was distributed in cytoplasm at metaphase during mitosis, and overexpression of SIRT1 significantly augmented apoptosis for cells at metaphase. In summary, we found SIRT1 is able to localize in cytoplasm, and cytoplasm-localized SIRT1 enhances apoptosis.


A radiofluorinated divalent cystine knot peptide for tumor PET imaging.
A divalent knottin containing two separate integrin binding epitopes (RGD) in the adjacent loops, 3-4A, was recently developed and reported in our previous publication. In the current study, 3-4A was radiofluorinated with a 4-nitrophenyl 2-(18)F-fluoropropinate ((18)F-NFP) group and the resulting divalent positron emission tomography (PET) probe, (18)F-FP-3-4A, was evaluated as a novel imaging probe to detect integrin αvβ3 positive tumors in living animals. Knottin 3-4A was synthesized by solid phase peptide synthesis, folded, and site-specifically conjugated with (18/19)F-NFP to produce the fluorinated peptide (18/19)F-fluoropropinate-3-4A ((18/19)F-FP-3-4A). The stability of (18)F-FP-3-4A was tested in both phosphate buffered saline (PBS) buffer and mouse serum. Cell uptake assays of the radiolabeled peptides were performed using U87MG cells. In addition, small animal PET imaging and biodistribution studies of (18)F-FP-3-4A were performed in U87MG tumor-bearing mice. The receptor targeting specificity of the radiolabeled peptide was also verified by coinjecting the probe with a blocking peptide cyclo(RGDyK). Our study showed that (18)F-FP-3-4A exhibited excellent stability in PBS buffer (pH 7.4) and mouse serum. Small animal PET imaging and biodistribution data revealed that (18)F-FP-3-4A exhibited rapid and good tumor uptake (3.76 ± 0.59% ID/g and 2.22 ± 0.62% ID/g at 0.5 and 1 h, respectively). (18)F-FP-3-4A was rapidly cleared from the normal tissues, resulting in excellent tumor-to-normal tissue contrasts. For example, liver uptake was only 0.39 ± 0.07% ID/g and the tumor to liver ratio was 5.69 at 1 h p.i. Furthermore, coinjection of cyclo(RGDyK) with (18)F-FP-3-4A significantly inhibited tumor uptake (0.41 ± 0.12 vs 1.02 ± 0.19% ID/g at 2.5 h) in U87MG xenograft models, demonstrating specific accumulation of the probe in the tumor. In summary, the divalent probe (18)F-FP-3-4A is characterized by rapid and high tumor uptake and excellent tumor-to-normal tissue ratios. (18)F-FP-3-4A is a highly promising knottin based PET probe for translating into clinical imaging of tumor angiogenesis.


Carbon and carbon composites obtained using deep eutectic solvents and aqueous dilutions thereof.
The aim of this featured article is to illustrate some of the most recent applications of deep eutectic solvents (DESs) in the synthesis of carbon and carbon composites. DESs can be obtained by the complexation of quaternary ammonium salts with hydrogen-bond donors. DESs have typically been referred to as a related class of ionic liquids because they share many properties. However, DESs present the advantage of easier and low-cost preparation. Moreover, their compositional flexibility can eventually be translated into materials that provide advanced functionalities and/or tailored hierarchical structures. Interestingly, the use of the liquid binary mixtures of DESs and H2O for the preparation of carbon materials plays a critical role with regard to the achievement of some particular porous morphologies. Herein, we will also summarize some recent studies performed on DES/H2O liquid binary mixtures, revealing the possibility of obtaining new eutectic mixtures upon the simple addition of water to DESs while keeping the DES contents at a certain pseudo-concentrated range. This finding will pave the way to novel applications, especially in those fields in which the preparation of high-tech products via low-cost processes is critical. We hope that this featured article will encourage scientists to explore the promising perspectives offered by DESs and aqueous dilutions thereof.


Patterns of Sexual Harassment: An Intersectional Approach to Reported Victimization in a Campus Climate Survey of Students at Irish Higher Education Institutions.
This study explores how identifying with multiple minority groups relates to sexual harassment victimization (SHV) among students in higher education institutions in Ireland (n = 6,002). Results show that gender nonconforming and female students were more likely than males to experience SHV. Bisexual or queer and gay or lesbian students were more likely than their heterosexual peers to experience SHV. Students with a physical or cognitive disability were more likely to experience SHV than those who reported no disability, and white students were more likely than minority ethnic groups to experience SHV. When controlling for sexual orientation, gender, and disability status, students who identified as both gay and lesbian and reported a cognitive disability were 8.5 times more likely to experience SHV. Victims of SHV reported having lower scores on perceived institutional support items than those who had not experienced SHV.