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We recently built the G4Jy-3CRE catalog of extragalactic radio sources. This catalog lists 264 powerful radio sources selected with similar criteria to those of the revised Third Cambridge Catalog, but visible from the Southern Hemisphere. A literature search revealed that 119 sources in the G4Jy-3CRE catalog (i.e., 45%) lack a firm spectroscopic redshift measurement. Here, we present a campaign aimed at acquiring optical spectra of G4Jy-3CRE sources and measuring their redshifts. We used single-slit observations obtained with the Víctor Blanco Telescope, the New Technology Telescope, the Southern Astrophysical Research Telescope, and the 2.1 m telescope of the Observatorio Astronómico Nacional at San Pedro Mártir, Mexico. In addition, we analyzed Very Large Telescope/MUSE archival observations. From these observations, we report the spectra and redshifts of 93 sources, 42 of which are the first optical spectra and redshift determinations for the respective sources. With our new data, approximately 71% of the sources in the G4Jy-3CRE catalog now have firm spectroscopic redshift measurements. This data set will be the basis of our future analysis of the optical properties of the G4Jy-3CRE catalog.

Since the early sixties, our view of radio galaxies and quasars has been drastically shaped by discoveries made thanks to observations of radio sources listed in the Third Cambridge Catalog and its revised version (3CR). However, the largest fraction of data collected to date on 3CR sources was performed with relatively old instruments, rarely repeated and/or updated. Importantly, the 3CR contains only objects located in the Northern Hemisphere, thus having limited access to new and innovative astronomical facilities. To mitigate these limitations, we present a new catalog of powerful radio sources visible from the Southern Hemisphere, extracted from the GLEAM 4 Jy (G4Jy) catalog and based on equivalent selection criteria as the 3CR. This new catalog, named G4Jy-3CRE, where the E stands for “equivalent,” lists a total of 264 sources at decl. below −5° and with 9 Jy limiting sensitivity at ∼178 MHz. We explored archival radio maps obtained with different surveys and compared them with optical images available in the Pan-STARRS, DES, and DSS databases to search for optical counterparts of their radio cores. We compared mid-infrared counterparts, originally associated in the G4Jy, with the optical ones identified here, and we present results of a vast literature search carried out to collect redshift estimates for all G4Jy-3CRE sources resulting in a total of 145 reliable z measurements.

We recently constructed the G4Jy-3CRE, a catalog of extragalactic radio sources based on the GLEAM 4-Jy (G4Jy) sample, with the aim of increasing the number of powerful radio galaxies and quasars with similar selection criteria to those of the revised release of the Third Cambridge Catalog (3CR). The G4Jy-3CRE consists of a total of 264 radio sources mainly visible from the Southern Hemisphere. Here, we present an initial X-ray analysis of 89 G4Jy-3CRE radio sources with archival X-ray observations from the Neil Gehrels Swift Observatory. We reduced a total of 624 Swift observations, for about 0.9 Ms of integrated exposure time. We found X-ray counterparts for 59 radio sources belonging to the G4Jy-3CRE, nine of them showing extended X-ray emission. The remaining 30 sources do not show any X-ray emission associated with their radio cores. Our analysis demonstrates that X-ray snapshot observations, even if lacking uniform exposure times, as those carried out with Swift, allow us to (i) verify and/or refine the host galaxy identification; (ii) discover the extended X-ray emission around radio galaxies of the intracluster medium when harbored in galaxy clusters, as the case of G4Jy 1518 and G4Jy 1664; and (iii) detect X-ray radiation arising from their radio lobes, as for G4Jy 1863.

Massive, quiescent galaxies are already observed at redshift z ∼ 4, i.e., ∼1.5 Gyr after the big bang. Current models predict them to be formed via massive, gas-rich mergers at z > 6. Recent ALMA observations of the cool gas and dust in z ≳ 6 quasars have discovered [C ii]- and far-infrared-bright galaxies adjacent to several quasars. In this work, we present sensitive imaging and spectroscopic follow-up observations, with HST/WFC3, Spitzer/IRAC, VLT/MUSE, Magellan/FIRE, and LBT/LUCI-MODS, of ALMA-detected, dust-rich companion galaxies of four quasars at z ≳ 6, specifically acquired to probe their stellar content and unobscured star formation rate. Three companion galaxies do not show significant emission in the observed optical/IR wavelength range. The photometric limits suggest that these galaxies are highly dust-enshrouded, with unobscured star formation rates SFRUV < few M⊙ yr−1, and a stellar content of M* < 1010M⊙ yr−1. However, the companion to PJ167−13 shows bright rest-frame UV emission (F140W AB = 25.48). Its spectral energy distribution resembles that of a star-forming galaxy with a total SFR ∼ 50 M⊙ yr−1 and M* ∼ 9 × 109M⊙. All the companion sources are consistent with residing on the galaxy main sequence at z ∼ 6. Additional, deeper data from future facilities, such as the James Webb Space Telescope, are needed in order to characterize these gas-rich sources in the first gigayear of cosmic history. [ABSTRACT FROM AUTHOR]

Quasars are galaxies hosting accreting supermassive black holes; due to their brightness, they are unique probes of the early universe. To date, only a few quasars have been reported at (<800 Myr after the big bang). In this work, we present six additional quasars discovered using the Pan-STARRS1 survey. We use a sample of 15 quasars to perform a homogeneous and comprehensive analysis of this highest-redshift quasar population. We report four main results: (1) the majority of quasars show large blueshifts of the broad C iv λ1549 emission line compared to the systemic redshift of the quasars, with a median value ∼3× higher than a quasar sample at ; (2) we estimate the quasars’ black hole masses ( (0.3–5) × 109M⊙) via modeling of the Mg ii λ2798 emission line and rest-frame UV continuum and find that quasars at high redshift accrete their material (with ) at a rate comparable to a luminosity-matched sample at lower redshift, albeit with significant scatter (0.4 dex); (3) we recover no evolution of the Fe ii/Mg ii abundance ratio with cosmic time; and (4) we derive near-zone sizes and, together with measurements for quasars from recent work, confirm a shallow evolution of the decreasing quasar near-zone sizes with redshift. Finally, we present new millimeter observations of the [C ii] 158 μm emission line and underlying dust continuum from NOEMA for four quasars and provide new accurate redshifts and [C ii]/infrared luminosity estimates. The analysis presented here shows the large range of properties of the most distant quasars. [ABSTRACT FROM AUTHOR]

Bright quasars, observed when the universe was less than one billion years old (z > 5.5), are known to host massive black holes (∼109M⊙) and are thought to reside in the center of massive dark matter overdensities. In this picture, overdensities of galaxies are expected around high-redshift quasars. However, observations based on the detection of Lyman-break galaxies (LBGs) around these quasars do not offer a clear picture: this may be due to the uncertain redshift constraints of LBGs, which are solely selected through broadband filters. To circumvent such uncertainties, we here perform a search for Lyman-alpha emitting galaxies (LAEs) in the field of the quasar PSO J215.1512–16.0417 at z ∼ 5.73, through narrowband deep imaging with FORS2 at the Very Large Telescope. We study an area of 37 arcmin2, i.e., ∼206 comoving Mpc2 at the redshift of the quasar. We find no evidence of an overdensity of LAEs in the quasar field with respect to blank-field studies. Possible explanations for these findings may be that our survey volume is too small, or that the strong ionizing radiation from the quasar hinders galaxy formation in its immediate proximity. Another possibility is that these quasars are not situated in the dense environments predicted by some simulations. [ABSTRACT FROM AUTHOR]

Background: Physical prehabilitation is recommended before major abdominal surgery to ameliorate short-term outcomes., Methods: A frequentist, random-effects network meta-analysis (NMA) was performed to clarify which type of preoperative physical activity among aerobic exercise (AE), inspiratory muscle training (IMT), and resistance training produces benefits in patients who underwent major abdominal surgery. The surface under the P-score, odds ratio (OR), or mean difference (MD) with a 95% confidence interval (CI) were reported. The results were adjusted by using the component network approach. The critical endpoints were overall and major morbidity rate and mortality rate. The important but not critical endpoints were the length of stay (LOS) and pneumonia., Results: The meta-analysis included 25 studies. The best approaches for overall morbidity rate were AE and AE + IMT (OR = 0.61, p-score = 0.76, and OR = 0.66, p-score = 0.68). The best approaches for pneumonia were AE + IMT and AE (OR = 0.21, p-score = 0.91, and OR = 0.52, p-score = 0.68). The component analysis confirmed that the best incremental OR (0.30; 95% CI 0.12-0.74) could be obtained using AE + IMT. The best approach for LOS was AE alone (MD - 1.63 days; 95% CI - 3.43 to 0.18). The best combination of components was AE + IMT (MD - 1.70; 95% CI - 2.06 to - 1.27)., Conclusions: Physical prehabilitation reduces the overall morbidity rate, pneumonia, and length of stay. The most relevant effect of prehabilitation requires the simultaneous use of AE and IMT., (© 2023. The Author(s).)

Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old 1 . How these black holes formed in such a short time is the subject of debate, particularly as they lie above the correlation between black-hole mass and galaxy dynamical mass 2,3 in the local Universe. What slowed down black-hole growth, leading towards the symbiotic growth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver 4 . Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 ≲ z ≲ 6.6. About half of the quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflow velocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z ≳ 5.8 is ≈2.4 times higher than at z ≈ 2-4. We infer that outflows at z ≳ 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z ≳ 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion 5 ., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: To assess use of self-monitoring of blood glucose (SMBG) in type 2 diabetes (T2DM) in the context of a continuous quality improvement initiative (AMD Annals)., Methods: 14 quality-of-care indicators were developed, including frequency of SMBG, fasting blood glucose (FBG), and post-prandial glucose (PPG) levels, and hypoglycemia and hyperglycemia episodes. Clinical data and SMBG values downloaded from any glucose meter were obtained from electronic medical records. The most frequently used glucose-lowering treatment regimens were identified and the indicators were assessed separately by regimen., Results: Overall, 21 Italian centers and 13,331 patients (accounting for 35,657 HbA1c tests and 8.44 million SMBG values collected during 2014 and 2015) were included in the analysis; 11 therapeutic regimens were selected. Patients in regimens not including insulin performed 15-23 measurements per patient-month, those treated with basal insulin 32.1 tests/patient-month, and those treated with basal and short-acting insulin 53-58 tests/patient-month. In all treatment regimens, PPG measurements represented a minority of all tests; pre-breakfast measurements accounted for about 50% of all FBG values. Mean FBG levels exceeded 130 mg/dl in 49.3-88.3% of the cases in the different treatment regimens, while PPG levels were over 140 mg/dl in 46.7-81.0%. From 5.7 to 32.7%, patients in the different regimens had at least one episode of hypoglycemia (< 70 mg/dl), while from 3.7 to 47.7% had at least one episode of hyperglycemia (> 300 mg/dl)., Conclusions: SMBG is underutilized in patients with T2DM treated or not with insulin. In all treatment groups, PPG is seldom investigated. Poor metabolic control and rates of hyper- and hypoglycemia deserve consideration in all treatment groups.

Quasars are the most luminous non-transient objects known and as a result they enable studies of the Universe at the earliest cosmic epochs. Despite extensive efforts, however, the quasar ULAS J1120 + 0641 at redshift z = 7.09 has remained the only one known at z > 7 for more than half a decade. Here we report observations of the quasar ULAS J134208.10 + 092838.61 (hereafter J1342 + 0928) at redshift z = 7.54. This quasar has a bolometric luminosity of 4 × 10 13 times the luminosity of the Sun and a black-hole mass of 8 × 10 8 solar masses. The existence of this supermassive black hole when the Universe was only 690 million years old-just five per cent of its current age-reinforces models of early black-hole growth that allow black holes with initial masses of more than about 10 4 solar masses or episodic hyper-Eddington accretion. We see strong evidence of absorption of the spectrum of the quasar redwards of the Lyman α emission line (the Gunn-Peterson damping wing), as would be expected if a significant amount (more than 10 per cent) of the hydrogen in the intergalactic medium surrounding J1342 + 0928 is neutral. We derive such a significant fraction of neutral hydrogen, although the exact fraction depends on the modelling. However, even in our most conservative analysis we find a fraction of more than 0.33 (0.11) at 68 per cent (95 per cent) probability, indicating that we are probing well within the reionization epoch of the Universe.

Background: The role of polyphenol intake on cardiovascular risk factors is little explored, particularly in people with diabetes., Aim: To evaluate the association between the intake of total polyphenols and polyphenol classes with the major cardiovascular risk factors in a population with type 2 diabetes., Methods: Dietary habits were investigated in 2573 males and females participants of the TOSCA.IT study. The European Prospective Investigation on Cancer and Nutrition (EPIC) questionnaire was used to assess dietary habits. In all participants, among others, we assessed anthropometry, plasma lipids, blood pressure, C-reactive protein and HbA1c following a standard protocol. The USDA and Phenol-Explorer databases were used to estimate the polyphenol content of the habitual diet., Results: Average intake of polyphenols was 683.3 ± 5.8 mg/day. Flavonoids and phenolic acids were the predominant classes (47.5% and 47.4%, respectively). After adjusting for potential confounders, people with the highest intake of energy-adjusted polyphenols (upper tertile) had a more favorable cardiovascular risk factors profile as compared to people with the lowest intake (lower tertile) (BMI was 30.7 vs 29.9 kg/m 2 , HDL-cholesterol was 45.1 vs 46.9 mg/dl, LDL-cholesterol was 103.2 vs 102.1 mg/dl, triglycerides were 153.4 vs 148.0 mg/dl, systolic and diastolic blood pressure were respectively 135.3 vs 134.3 and 80.5 vs 79.6 mm/Hg, HbA1c was 7.70 vs 7.67%, and C-reactive Protein was 1.29 vs 1.25 mg/dl, p < .001 for all). The findings were very similar when the analysis was conducted separately for flavonoids or phenolic acids, the two main classes of polyphenols consumed in this population., Conclusions: Polyphenol intake is associated with a more favorable cardiovascular risk factors profile, independent of major confounders. These findings support the consumption of foods and beverages rich in different classes of polyphenols particularly in people with diabetes., Clinical Trial: http://www.clinicaltrials.gov; Study ID number: NCT00700856., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Diabetes and depression are reciprocally linked, but few studies modeled their interplay considering the influence of affective temperaments (AT) and demographic factors., Methods: Participants with type 1 and type 2 diabetes (T1DM and T2DM, n=279) recruited from Diabetes Units were assessed with the Beck Depression Inventory (BDI), Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A), Morisky Medication Adherence Scale (MMAS), Diabetes Distress Scale (DDS) and Cumulative Illness Rating Scales (CIRS). Glycosylated hemoglobin levels (HBA1C) was used as index of glycemic control. The bi-directional association between glycemic control, depression and candidate mediators was examined with Structural Equation Modeling, testing the impact of moderator variables (AT, diabetes type, age and gender) with multigroup comparison., Results: The association between HBA1C and depressive symptoms was mediated by diabetes-related distress,, while there was no definite evidence of depression influencing HBA1C through changes of adherence, tiredness, appetite, alcohol intake or smoking. Among individuals with AT, distress was unrelated to HBA1C and had a higher impact on depression; adherence was inversely association with HBA1C. Moreover, physical comorbidities impacted on depression. While diabetes type had a moderation role, age and gender did not affect the model., Limitations: Cross sectional design, lack of objective measures of diet and physical activity., Conclusions: Glycemic control seem to influence the severity of depressive symptoms, but the reciprocal association seems non-significant. AT and diabetes type may shape this relationship influencing distress and adherence to medications. Findings may aid interventions aimed at improving patients' care and quality of life., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The existence of massive (10 11 solar masses) elliptical galaxies by redshift z ≈ 4 (refs 1, 2, 3; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation rates exceeding 100 solar masses per year at z > 6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower. The only known galaxies with very high star-formation rates at z > 6 are, with one exception, the host galaxies of quasars, but these galaxies also host accreting supermassive (more than 10 9 solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon ([C ii] at a wavelength of 158 micrometres) in four galaxies at z > 6 that are companions of quasars, with velocity offsets of less than 600 kilometres per second and linear offsets of less than 100 kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the [C ii] measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in [C ii] brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift. We find such close companions in four out of the twenty-five z > 6 quasars surveyed, a fraction that needs to be accounted for in simulations. If they are representative of the bright end of the [C ii] luminosity function, then they can account for the population of massive elliptical galaxies at z ≈ 4 in terms of the density of cosmic space.

Background and Aims: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes., Methods and Results: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women., Conclusions: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet-within the ranges recommended by different guidelines-with metabolic risk factors., Methods: We studied 1785 people with type 2 diabetes, aged 50-75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured., Results: Increasing fat intake from <25 to ≥35 % is associated with a significant increase in LDL-cholesterol, triglycerides, HbA1c and CRP (p < 0.05). Increasing carbohydrates intake from <45 to ≥60 % is associated with significantly lower triglycerides, HbA1c and CRP (p < 0.05). A fiber intake ≥15 g/1000 kcal is associated with a better plasma lipids profile and lower HbA1c and CRP than lower fiber consumption. A consumption of added sugars of ≥10 % of the energy intake is associated with a more adverse plasma lipids profile and higher CRP than lower intake., Conclusions: In people with type 2 diabetes, variations in the proportion of fat and carbohydrates of the diet, within the relatively narrow ranges recommended by different nutritional guidelines, significantly impact on the metabolic profile and markers of low-grade inflammation. The data support the potential for reducing the intake of fat and added sugars, preferring complex, slowly absorbable, carbohydrates.

Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.

This article explores the interplay of ethnicity and sexuality in poet Rose Romano's work, especially as she engages in a complex, and, at times, highly debatable identity politics. In her poetry, Romano denounces the oppression she experiences as a lesbian, a Sicilian American, and even as an "Olive" ethnic in the lesbian publishing community. Particularly interesting is her strained relationship with the multicultural lesbian community due to disagreements around the concept of race, and, consequently, of racial hierarchies. With her poetry, Rose Romano questioned all kinds of categorizations that do not take into account the complexities of her multi-faceted identity.

To determine the clinical impact of conversion from C0 to C2 Neoral monitoring, we conducted a 6-month prospective study in 62 stable renal transplant recipients. Neoral was given alone (19%), with steroids (31%), combined with azathioprine (Aza) or mycophenolate mofetil (MMF) (50%). C0 and C2 target ranges were, respectively, 130-190 and 700-900 ng/mL. Neoral dosages were adjusted according to the C2 range. At baseline, mean C0 and C2 were 157 and 762 ng/mL. After 6 months C0 was 173 ng/mL (p<0.02) and C2 was 804 ng/mL (ns). Although the mean Neoral dose at 6 months was unchanged from baseline, the dose was reduced in 24 patients from 3.6+/-1.2 to 3.0+/-0.9 mg/kg/day, with a mean reduction in serum creatinine (Cr) from 1.4+/-0.4 to 1.3+/-0.3 mg/dL (p<0.001), stable in 8 patients and increased in 30 patients from 3.3+/-1.0 to 3.8+/-1.2 mg/kg/day with no change in serum Cr. Serum transaminases and blood pressure (BP) were unchanged in the three groups. C0 and C2 showed a positive correlation, but with a large dispersion of values (r2=0.14, p<0.001). Overall concordance between the C0 and C2 ranges was 49%. Therefore, in stable transplant patients C0 cannot be considered a C2 surrogate. The conversion from C0 to C2 led to a Neoral dose reduction in approximately 40% of patients with significant improvement in renal function. Most of the remaining patients required an increased dose; however, without an increased incidence of cyclosporin-induced side-effects.

Cholesterol embolic disease in the renal allograft is not recognized as an important cause of graft dysfunction. We describe here two renal transplant patients with cholesterol embolization in their allograft biopsies. The first, a 48-year-old patient, received a renal transplant from a 62-year-old donor with a history of hypertension and tobacco use. On account of initial non-function, a renal biopsy was taken, which showed acute tubular necrosis and cholesterol emboli. The second, a 55-year-old man, presented chronic allograft failure six years after transplantation; ultrasonography showed a solid renal mass. Nephrectomy specimens revealed renal carcinoma and a combination of chronic rejection and multiple cholesterol emboli. Cholesterol embolic disease is probably an under-reported cause of renal graft dysfunction. The source of the emboli may be either the donor or the recipient's vessels. Since the current tendency is to accept older donors and recipients with more advanced atherosclerotic disease, this condition is likely to become more frequent in the future. Particular care must be taken at the time of organ procurement and during the evaluation of organ donors, in order to reduce the risk of embolization.

Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.

Background: Primary Sjögren's syndrome is a connective tissue disorder affecting primarily the lacrimal and salivary glands, resulting in xerophtalmia and xerostomia. Extraglandular manifestations are frequent and may include renal involvement., Methods: We studied the prevalence and nature of kidney involvement in 60 Italian patients with primary Sjögren's syndrome, diagnosed according to the European classification criteria. The following renal laboratory tests were performed in all patients: electrolytes in serum and in 24-h urine, creatinine in serum and in 24-h urine, venous pH and HCO(3)(-), urinalysis, urine culture, urinary osmolality and urine pH. A water deprivation test was performed in patients with morning urine osmolalities below the reference values adjusted for age. An oral ammonium chloride loading test was performed in patients with urine pH above 5.5 from morning samples. Renal biopsy was performed in patients with renal involvement., Results: Sixteen patients (27%) had laboratory evidence of tubular and/or glomerular dysfunction. A variable degree of creatinine clearance reduction was found in eight patients (13%); frank distal tubular acidosis in three (5%); hypokalaemia in four (7%); and pathological proteinuria in 12 (20%). Urine concentrating capacity was defective in 10 out of 48 (21%) tested patients. Only four patients presented with overt clinical manifestations, including hypokalaemic tetraparesis (1), nephrotic syndrome (2), recurrent renal stones with flank pain and haematuria (1). In two patients, signs of renal involvement preceded the onset of sicca syndrome. Renal biopsies from nine patients showed tubulo-interstitial nephritis in six and glomerular disease in three. Patients with renal involvement had a significantly shorter disease duration compared with patients without renal abnormalities., Conclusions: Kidney involvement is a frequent extraglandular manifestation of primary Sjögren's syndrome. It is rarely overt and may precede the onset of subjective sicca syndrome.

Ras-related guanosine triphosphatases (GTPases) couple receptor activity to a number of intracellular signalling events culminating in the control of cell morphology and gene transcription. In culture cells, the best-understood Ras-dependent signalling pathway involves the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) cascade. A growing body of evidence has recently been accumulating to suggest a crucial role of Ras and MAPK signalling in neuronal functions connected to synaptic plasticity. In the present review article we discuss the experimental basis supporting the notion that the Ras/MAPK pathway interacts with other synaptic mechanisms to regulate invertebrate and vertebrate behavioural responses such as those implicated in learning and memory processes.

Various transcription factors act as nuclear effectors of the cAMP-dependent signaling pathway. These are the products of three genes in the mouse, CREB, CRE modulator (CREM), and ATF-1. CREM proteins are thought to play important roles within the hypothalamic-pituitary axis and in the control of rhythmic functions in the pineal gland. We have generated CREM-mutant mice and investigated their response in a variety of behavioral tests. CREM-null mice show a drastic increase in locomotion. In contrast to normal mice, the CREM-deficient mice show equal locomotor activity during the circadian cycle. The anatomy of the hypothalamic suprachiasmatic nuclei, the center of the endogenous pacemaker, is normal in mutant mice. Remarkably, CREM mutant mice also elicit a different emotional state, revealed by a lower anxiety in two different behavioral models, but they preserve the conditioned reactiveness to stress. These results demonstrate the high degree of functional specificity of each cAMP-responsive transcription factor in behavioral control.

The cAMP signalling pathway plays a key role in the regulation of the hypothalamic-pituitary-adrenal axis. Transcription factor CREM (cAMP response element modulator) is implicated in the modulation of a number of neuroendocrine functions. By virtue of an alternative, intronic promoter CREM generates the powerful transcriptional repressor ICER (inducible cAMP early repressor), which displays a pronounced neuroendocrine-specific expression. Here we document a remarkable induction of ICER in response to acute stress in the intermediate lobe (IL) of the pituitary gland. The induction is transient and is preceded by CREB phosphorylation. Adrenergic stimulation directs ICER induction in the IL through the activation of both beta2-adrenergic and corticotrophin-releasing hormone receptors. These receptors are positively coupled to the adenylate cyclase signalling pathway, which regulates hormone release from the IL, implicating ICER in the modulation of peptide secretion. We show that targeted ablation of the CREM gene in the mouse causes a chronic increase of beta-endorphin levels. Altered hormonal production occurs both in basal conditions and after stress. Thus, early ICER induction in the IL may be involved in the modulation of gene expression in response to stress.

1. Mouse fibroblasts (NIH3T3) transfected with the full-length coding region of the Mel1a melatonin receptor stably expressed the receptor, coupled to a pertussis toxin-sensitive G-protein(s) and exhibiting high affinity and adequate pharmacological profile. 2. The receptor protein had the tendency of a strong coupling to the G-protein and therefore low-affinity state was induced by uncoupling the receptor from its G-protein in presence of high concentrations of NaCl (500-700 mM) and/or GTPgammaS (100 microM). Thereafter, the affinity of a series of melatonin analogues was determined to both, high- and low-affinity receptor states, thus providing a basis for the prediction of their efficacy, according to the ternary complex model. 3. The cells were subsequently used to study the agonist-induced G-protein activation, determined by calculating the rate of GDP-GTP exchange measured in presence of 35S-labelled GTPgammaS. The natural ligand melatonin induced a significant increase in the GDP-GTP exchange rate, the presence of GDP and NaCl being necessary to observe this effect. 4. The full agonists 2-phenylmelatonin, 2-bromomelatonin and 6-chloromelatonin equally induced an increase of the GDP-GTP exchange. 5-Hydroxy-N-acetyltryptamine activated the GTP-GDP exchange to a much lesser extent (53%) than melatonin, thus behaving as a partial agonist. As predicted by the model, the melatonin antagonist (N-[(2-phenyl-1H-indol-3-yl)ethyl]cyclobutanecarboxamide) was without effect on basal G protein activation. Coincubation of this compound with melatonin induced a dose-dependent rightward shift in the melatonin concentration-effect curve, thus exhibiting the behaviour of a competitive and surmountable antagonist. 5. Using the equation proposed by Venter (1997) we were able to determine that there were no 'spare' receptors in the system. Therefore, the approach proposed in the present work can be successfully used for the determination of 'drug action' at the level of the human Mel1a melatonin receptor and evaluation of the efficacy of new selective melatonin analogues.

The adult human cerebellum expresses melatonin receptors with high density in the external zone of the molecular layer. Cloning of the receptor cDNA isolated by RT-PCR from human cerebellar specimens and sequencing analysis of the full-length coding region revealed that the receptor protein is encoded by a transcript identical to that recently cloned from the human hypothalamus (Mel1a). In situ hybridization using an antisense cRNA-probe demonstrated that the melatonin receptor mRNA is localized in the cerebellar granule cells. Mapping of the messenger by RT-PCR with Mel1a specific primers in different areas of the human brain disclosed a quite widespread distribution of the transcript, although expressed at very low levels. Semi-quantitative comparison between the different brain regions allowed to establish the following relative mRNA abundance: cerebellum > or = occipital cortex > or = parietal cortex > temporal cortex > thalamus > frontal cortex > or = hippocampus. No mRNA was detected in white blood cells.

The CREM gene encodes both repressors and activators of cAMP-dependent transcription in a tissue and developmentally regulated manner. In addition, multiple and cooperative phosphorylation events regulate the function of the CREM proteins. CREM plays a key physiological and developmental role within the hypothalamic-pituitary axis. There is a functional switch in CREM expression during the development of male germ cells which is directed by the pituitary hormone FSH. The CREM protein in germ cells is a powerful activator which appears to function as a master-switch in the regulation of postmeiotic genes. CREM is inducible by activation of the cAMP signalling pathway with the kinetics of an early response gene. The induction is transient, cell-specific, does not involve increased transcript stability and does not require protein synthesis. The subsequent decline in CREM expression requires de novo protein synthesis. The induced transcript encodes ICER and is generated from an alternative, intronic promoter. ICER functions as a powerful repressor of cAMP-induced transcription, and represses the activity of its own promoter, thus constituting a negative autoregulatory loop.

Reverse transcription-polymerase chain reaction (RT-PCR) analysis performed on total RNA from different tissues of Xenopus laevis showed that the melatonin receptor gene cloned from dermal melanophores is expressed in the whole brain, skin, and retina, and that apart from the ovary, there is no expression in tissues having origin outside the central nervous system. Comparative studies using in vitro autoradiography and in situ hybridization demonstrated that the melatonin receptor is expressed with discrete allocation in Xenopus brain. Though the distribution pattern of the specific messenger RNA conforms well with that of the corresponding receptor protein, it is not always coincident.

Naturally occurring nondeletional mutations affecting the distal CCAAT box of the human gamma-globin gene promoter result in hereditary persistence of fetal hemoglobin in adult life. Although the distal CCAAT box is the target of several factors, including CP1/NFY, CDP, GATA-1 and NFE3, only NFE3 binding activity is consistently sensitive to well characterized mutations in this region such as G-117-->A, C-114-->T, and delta 13 hereditary persistence of fetal hemoglobin. We extensively characterized the binding specificities of NFE3 and demonstrated that NFE3 has unique properties with respect to other CCAAT box-binding proteins. Affinity-purified NFE3 from erythroid K562 cells binds the distal but not the proximal human gamma-globin CCAAT box, the single CCAAT box of the human epsilon-globin promoter, and the proximal CCAAT box of the evolutionarily related Galago crassicaudatus gamma-globin gene. Within the epsilon-globin CCAAT box, NFE3 represents the major and almost exclusive binding activity. Disruption of such a binding site essentially inactivates the epsilon-globin promoter, suggesting that NFE3 plays an important role in the embryonic expression of this gene.