Phenomenology of Somatization in Immigrants: An Idealtypical Approach.

INTRODUCTION: Somatization in immigrants is frequent but standard studies do not differentiate between various forms of somatization. In this qualitative study, we used an idealtypical approach with the aim of phenomenologically differentiating between different forms of somatization in immigrants. METHODS: The clinical description of the ideal types was based on seven levels: medical examination; description of somatization symptoms; the patients' own interpretation of their somatic experience; concomitant psychopathological phenomena; genetic understanding; clinician's interpretation; and course and treatment. RESULTS: Five different ideal typologies of patients emerged: anxious hypochondriasis, somatization with cultural features playing a pathogenetic role, culturally shaped somatization (through pathoplastic effects), somatization as part of adjustment reactions due to migratory living difficulties, and somatization as post-traumatic reaction. CONCLUSION: These differences are useful to highlight the complex interrelationship between socioeconomic, migratory, cultural, and value factors in the construction of somatization among immigrants. Implications for research methodology, nosology, clinical management, and organization of medical facilities are also discussed.

Intracranial carotid artery calcification morphology differs in patients with lacunar and nonlacunar acute ischemic strokes.

BACKGROUND AND PURPOSE: Intracranial carotid artery calcifications (ICACs) are a common finding on noncontrast computed tomography (NCCT) and have been associated with an increased risk of ischemic stroke. However, no data are available about the association between ICAC patterns and stroke etiology. We investigated the association between ICAC patterns and etiological subtypes of ischemic stroke. METHODS: We retrospectively analyzed a single center cohort of patients admitted for ischemic stroke with known etiology. Each carotid artery was evaluated separately on NCCT scans to define the ICAC pattern (intimal, medial, mixed). The association between ICAC patterns and stroke etiology was investigated using logistic regression models adjusting for relevant confounders. RESULTS: A total of 485 patients were included (median age = 78 [interquartile range (IQR) = 70-85] years, 243 [50%] female, median National Institutes of Health Stroke Scale = 6 [IQR = 3-12]). Frequencies of ICAC patterns were: intimal, n = 96 (20%); medial, n = 273 (56%); mixed, n = 51 (11%), indistinct/absent, n = 65 (13%) patients. Intimal pattern was more frequent in lacunar compared with nonlacunar (33% vs. 16%, p < 0.001) stroke etiology, whereas medial pattern was less frequent in lacunar compared with nonlacunar stroke (36% vs. 62%, p < 0.001). After adjustment for confounders, intimal ICAC predominant pattern remained associated with lacunar stroke etiology in two multivariate models (Model 1: adjusted odds ratio [aOR] = 2.08, 95% confidence interval [CI] = 1.20-3.56; Model 2: aOR = 2.01, 95% CI = 1.16-3.46). CONCLUSIONS: Our study suggests that intimal ICAC pattern is associated with lacunar stroke and may serve as a marker for lacunar stroke etiology, possibly strengthening the relation between endothelial dysfunction and lacunar stroke.

Impact of CYP2C19 Genotype on Efficacy and Safety of Clopidogrel-based Antiplatelet Therapy in Stroke or Transient Ischemic Attack Patients: An Updated Systematic Review and Meta-analysis of Non-East Asian Studies.

PURPOSE: Inconclusive and limited results have been reported on the clinical utility of CYP2C19 genotyping in stroke/TIA patients of non-East Asian ancestries. We herein performed an updated systematic review and meta-analysis to quantitatively estimate the association of CYP2C19 loss-of function (LOF) status with efficacy and safety of clopidogrel-based antiplatelet therapy in non-East Asian patients affected by stroke or TIA. METHODS: A comprehensive search was performed up to July 2023 using PubMed, Web of Knowledge, and Cochrane Library databases. The clinical outcomes investigated were stroke, composite vascular events and bleeding. Pooled estimates were calculated as risk ratios (RR) with 95% CI using the Mantel- Haenszel random-effects model. The quality of evidence was assessed using the GRADEpro tool. RESULTS: A total number of 1673 stroke/TIA patients from 8 non-East Asian studies, published between 2014 and 2022, were included in the systematic review. Clopidogrel-treated carriers of CYP2C19 LOF alleles were found at increased risk of stroke compared to non-carriers (RR: 1.68, 95%CI: 1.04-2.71, P = 0.03). However, no significant association was observed with the risk of composite vascular events (RR: 1.15, 95%CI: 0.58-2.28, P = 0.69) or bleeding (RR: 0.84, 95%CI: 0.38-1.86, P = 0.67). Similarly, European ancestry patients carrying CYP2C19 LOF alleles displayed a higher risk of stroke (RR: 2.69 (1.11-6.51, P = 0.03), but not of composite vascular events or bleeding. CONCLUSION: The present updated meta-analysis provides moderate quality evidence of association between CYP2C19 LOF alleles and an increased risk of stroke in non-East Asian patients with stroke/TIA after receiving clopidogrel therapy. Further large pharmacogenetic studies are still warranted to corroborate these findings.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Clonidine and Brain Mitochondrial Energy Metabolism: Pharmacodynamic Insights Beyond Receptorial Effects.

Clonidine is an anti-hypertensive drug that inhibits the release of norepinephrine from pre-synaptic terminals binding to pre-synaptic α2-adrenoreceptors. Some studies suggest that this drug decreases brain energy expenditure, particularly in hypoxic-ischemic injury. However, data about clonidine effects on the functional parameters regulating brain energy metabolism are lacking. In this study, the effects of acute clonidine treatment (5 µg×kg-1 i.p., 30 min) were evaluated on the catalytic activity of regulatory energy-linked enzymes of Krebs' cycle, Electron Transport Chain and glutamate metabolism of temporal cerebral cortex of 3-month-old male Sprague-Dawley rats. Enzyme activities were assayed on non-synaptic "free" mitochondria (FM) of neuronal perikaryon and partly of glial cells, and on intra-synaptic "light" (LM) and "heavy" mitochondria (HM), localized within synaptic terminals. This subcellular analysis differentiates clonidine effects on post-synaptic and pre-synaptic neuronal compartments. The results showed that clonidine increased citrate synthase, cytochrome oxidase and glutamate-oxaloacetate transaminase activities of FM. In LM, citrate synthase activity was decreased, while cytochrome oxidase and glutamate-oxaloacetate transaminase activities were increased; on the contrary, citrate synthase, cytochrome oxidase and glutamate dehydrogenase were all decreased in HM. Therefore, clonidine exerted different effects with respect to brain mitochondria, coherently with the in vivo energy requirements of each synaptic compartment: the drug increased energy-linked enzyme activities in post-synaptic compartment, while the metabolic variations were complex in the pre-synaptic one, being enzyme activities heterogeneously modified in LM and decreased in HM. This study highlights the relationships existing between the clonidine-induced neuroreceptorial effects and the energy metabolism in pre- and post- synaptic bioenergetics.

The obesity paradox and diabetes.

BACKGROUND: Obesity has been proven to be a risk factor for type 2 diabetes mellitus (T2DM) through numerous pathogenetic mechanisms. Unexpectedly, some studies suggest that subjects with overweight/obesity and T2DM have better clinical outcome than their normal weight peers. This finding is described as "obesity paradox" and calls into question the importance of weight loss in this specific population. OBJECTIVE: This article is a narrative overview on the obesity and type 2 diabetes mellitus, particularly regarding the obesity paradox in T2DM patients. METHODS: We used as sources MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library, from inception to March 2020; we chose 30 relevant papers regarding the association of obesity with clinical outcome and mortality of patients affected by T2DM. RESULTS: Many studies report that in patients with T2DM, overweight and obesity are associated with a better prognosis than underweight or normal weight, suggesting the presence of an obesity paradox. However, these studies have numerous limitations due to their mainly retrospective nature and to numerous confounding factors, such as associated pathologies, antidiabetic treatments, smoking habit, lack of data about distribution of body fat or weight history. CONCLUSION: Literature data regarding the phenomenon of obesity paradox in T2DM patients are controversial due to the several limitations of the studies; therefore in the management of patients with overweight/obesity and T2DM is recommended referring to the established guidelines, which indicate diet and physical activity as the cornerstone of the treatment. LEVEL OF EVIDENCE: Level V: narrative review.

Detailed In Vitro Pharmacological Characterization of the Clinically Viable Nociceptin/Orphanin FQ Peptide Receptor Antagonist BTRX-246040.

The peptide nociceptin/orphanin FQ (N/OFQ) is the natural ligand of the N/OFQ receptor (NOP), which is widely expressed in the central and peripheral nervous system. Selective NOP antagonists are worthy of testing as innovative drugs to treat depression, Parkinson disease, and drug abuse. The aim of this study was to perform a detailed in vitro characterization of BTRX-246040 (also known as LY2940094, [2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol), a novel NOP antagonist that has been already studied in humans. BTRX-246040 has been tested in vitro in the following assays: calcium mobilization in cells expressing NOP and classic opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer assay measuring NOP interaction with G proteins and ß-arrestins, the label-free dynamic mass redistribution assay, and the electrically stimulated mouse vas deferens. BTRX-246040 was systematically compared with the standard NOP antagonist SB-612111. In all assays, BTRX-246040 behaves as a pure and selective antagonist at human recombinant and murine native NOP receptors displaying 3-10-fold higher potency than the standard antagonist SB-612111. BTRX-246040 is an essential pharmacological tool to further investigate the therapeutic potential of NOP antagonists in preclinical and clinical studies. SIGNIFICANCE STATEMENT: NOP antagonists may be innovative antidepressant drugs. In this research, the novel clinically viable NOP antagonist BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent, and selective NOP antagonist.

The treament of hyperglycemia in acute ischemic stroke with incretin-based drugs.

Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy. The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM. This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.

The Psychological Impact of Epidemic and Pandemic Outbreaks on Healthcare Workers: Rapid Review of the Evidence.

PURPOSE OF REVIEW: We aim to provide quantitative evidence on the psychological impact of epidemic/pandemic outbreaks (i.e., SARS, MERS, COVID-19, ebola, and influenza A) on healthcare workers (HCWs). RECENT FINDINGS: Forty-four studies are included in this review. Between 11 and 73.4% of HCWs, mainly including physicians, nurses, and auxiliary staff, reported post-traumatic stress symptoms during outbreaks, with symptoms lasting after 1-3 years in 10-40%. Depressive symptoms are reported in 27.5-50.7%, insomnia symptoms in 34-36.1%, and severe anxiety symptoms in 45%. General psychiatric symptoms during outbreaks have a range comprised between 17.3 and 75.3%; high levels of stress related to working are reported in 18.1 to 80.1%. Several individual and work-related features can be considered risk or protective factors, such as personality characteristics, the level of exposure to affected patients, and organizational support. Empirical evidence underlines the need to address the detrimental effects of epidemic/pandemic outbreaks on HCWs' mental health. Recommendations should include the assessment and promotion of coping strategies and resilience, special attention to frontline HCWs, provision of adequate protective supplies, and organization of online support services.

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.

BACKGROUND: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. METHODS: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. RESULTS: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. CONCLUSIONS: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Modulation of Drosophila suzukii type 1 tyramine receptor (DsTAR1) by monoterpenes: a potential new target for next generation biopesticides.

This study proposes a biochemical and molecular model for the interaction between the Drosophila suzukii type 1 tyramine receptor (DsTAR1) and monoterpenes. A preliminary molecular and functional characterization of DsTAR1 cDNA revealed that a 1.8 kb long ORF codes for a 600 amino acid polypeptide featuring seven transmembrane domains, as expected for a GPCR. A stable HEK 293 cell line expressing DsTAR1 was tested for responsiveness to tyramine (TA) and octopamine (OA). In intracellular calcium mobilization studies, TA led to a concentration-dependent increase in [Ca2+]i (pEC50 ~ 6.40), completely abolished by pre-incubation with the antagonist yohimbine 1 µM. Besides, in dynamic mass redistribution (DMR) studies, TA evoked a positive DMR signal in a concentration-dependent manner (pEC50 ~ 6.80). The recombinant cell line was then used to test three monoterpenes (thymol, carvacrol and α-terpineol) as putative ligands for DsTAR1. The terpenoids showed no agonist effects in both DMR and calcium mobilization assays, but they increased the potency of the endogenous ligand, TA, acting as positive allosteric modulators. Moreover, expression analysis on adults D. suzukii, exposed for 24, 72 or 120 h to a sublethal concentration of the three monoterpenes, showed a downregulation of DsTAR1. This evidence has led to hypothesize that the downregulation of DsTAR1 might be a compensatory mechanism in response to the positive allosteric modulation of the receptor induced by monoterpenes. Therefore, these findings might be useful for the development of a new generation of biopesticides against Drosophila suzukii, targeting TAR1.

Clinical Factors Influencing the Outcomes of an Acellular Dermal Matrix for Skin Cancer Treatment: A Retrospective Study.

OBJECTIVE: To evaluate the efficacy and safety of a biologically engineered dermal matrix used in reconstructive surgery after skin tumor resection, focusing on the frequency of successful grafting and identifying potential factors influencing treatment outcomes. DESIGN AND PARTICIPANTS: This retrospective analysis involved consecutive patients diagnosed with skin cancer in any area of the body and for which treatment with a dermal skin template was recommended as alternative to traditional surgery. MAIN OUTCOME MEASURES: Percentage of successful grafting and the patient and tumor characteristics influencing treatment outcome via univariate analysis. MAIN RESULTS: A total of 302 patients were included. Surgical reconstruction with the matrix was effective in 88.9% of the patients within 21 days of surgery. Notably, the matrix was successful regardless of tumor location, type, or size. Infection was the only variable significantly associated with graft failure (P < .001). CONCLUSIONS: The studied dermal matrix provides an efficient alternative to traditional reconstructive surgery in patients who present specific comorbidities or risk factors. The only variable significantly associated with graft failure was infection, which should be properly controlled through appropriate treatment.

Psychopathological and psychiatric evaluation of patients affected by lipodystrophy.

PURPOSE: Lipodystrophy is a collection of rare disorders defined by complete or partial loss of adipose tissue, due to abnormal adipocyte production, function, or distribution; it shares the main metabolic complications with obesity. Aims of the present study were to investigate the psychopathological characteristics of non-HIV lipodystrophic patients in comparison with a group of obese patients, a group of patients affected by oncologic chronic illness, and a control group of healthy subjects. METHODS: All participants were female: 16 non-HIV lipodystrophic women (mean age 42 ± 12 years), 20 women with breast cancer (adenocarcinoma with a positive sentinel lymph node in outpatients awaiting chemotherapy, mean age 44 ± 5 years), 20 obese women (mean age 40 ± 3 years), and 20 healthy women (mean age 40 ± 2 years). Each lipodystrophic patient received a psychiatric assessment, following the diagnostic criteria for DSM-5. Patients and controls received a battery of self-report instruments measuring general psychopathology, body image concerns, eating habits and food craving, and pain concerns. The following psychopathological rating scales were used: SCL-90-R (Symptom Check List) for general psychopathology, BUT (Body Uneasiness Test) for body image, FCQ-T (Food Cravings Questionnaire Trait) for food craving, and WHYMPI (West Haven Yale Multidimensional Pain Inventory) for multidimensional pain inventory. RESULTS: The psychiatric assessment of the 16 lipodystrophic patients revealed: three lifetime mood disorder, six current mood disorder, six lifetime anxiety disorder, five current anxiety disorder, four current somatic symptom disorder with predominant pain, six current binge eating disorder, 11 eating disorder not otherwise specified, two borderline personality disorder, one obsessive-compulsive personality disorder, one avoidant personality disorder, and five personality disorder not otherwise specified. In SCL-90-R scale, the subscale sensitivity showed a significantly higher score in the lipodystrophic and oncologic groups compared to healthy subjects. The subscale paranoid ideation showed a significantly higher score in the lipodystrophic group vs all the other groups. The total score of BUT scale was significantly higher in the lipodystrophic compared to healthy subjects. In WHYMPI scale, the scores of pain interference and family support were significantly higher in the lipodystrophic group. The scores of negative responses were significantly higher in the lipodystrophic group vs healthy subjects. In FCQ-T scale, the score of Cues dimension in lipodystrophic patients was significantly lower as compared with all the other groups. CONCLUSIONS: Our findings suggest that lipodystrophic patients have an increased prevalence of mood, anxiety, pain, and eating disorders. LEVEL OF EVIDENCE: Level III. Evidence obtained from case-control analytic study.

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year. RESULTS: We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. CONCLUSIONS: Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.

Tetrabranched Hetero-Conjugated Peptides as Bifunctional Agonists of the NOP and Mu Opioid Receptors.

The general aim of the work was the validation of a new synthetic methodology designed for obtaining bifunctional heterotetrabranched peptide ligands. Applying an easily accessible synthetic route, we provided a small series of heteromultimeric peptide conjugates targeting the nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) and mu opioid receptors. Among these, H-PWT1-N/OFQ-[Dmt1]dermorphin demonstrated a similar and high agonist potency at the NOP and mu receptors. The achieved results confirmed the robustness of the approach that is extremely versatile and virtually applicable to different peptide sequences whose pharmacological activity can be combined for generating dual acting multimeric compounds. These innovative pharmacological tools will be extremely helpful for investigating the consequences of the simultaneous activation and/or blockage of different peptidergic receptors.

Potential use of a diluted high-relaxivity gadolinium-based intra-articular contrast agent for magnetic resonance arthrography: an in-vitro study.

BACKGROUND: Magnetic resonance arthrography (MRA) requires intra-articular injection of gadolinium-based diluted paramagnetic contrast material. To our knowledge, gadobenate dimeglumine (Gd-BOPTA) has never been used for intra-articular applications. Our aim was to test in vitro different concentrations of Gd-BOPTA to be potentially used to perform MRA. METHODS: Gd-BOPTA was diluted in saline (NaCl 0.9%) to achieve different concentrations (4 mmol/l; 2 mmol/l; 1 mmol/l; 0.67 mmol/l; 0.5 mmol/l). Six sets of five sterile pipes were prepared with 5 ml of each solution, five sets added with 0.5 ml of fresh synovial fluid. Two separate pipes were prepared with 5 ml of gadopentetate dimeglumine (Gd-DTPA) at 2 mmol/l, one pipe added with 0.5 ml of synovial fluid. Pipes were imaged using a T1-weighted sequence at 1.5 T. For each pipe, signal intensity (SI) in arbitrary units (au) was measured. RESULTS: SI reproducibility range was 86-99%. Mean Gd-BOPTA SI in pipes containing synovial fluid increased from 1236 ± 8au (0.5 mmol/l) up to 1610 ± 44au (1 mmol/l) and down to 1405 ± 33au (4 mmol/l). Mean Gd-BOPTA SI in pipes without synovial fluid increased from 1184 ± 29au (0.5 mmol/l) up to 1530 ± 38au (1 mmol/l), and down to 1347 ± 39au (4 mmol/l). SI of pipes without synovial fluid was lower than that of pipes with synovial fluid for both Gd-BOPTA and Gd-DTPA (P ≤ 0.002). Regarding pipes with synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1246 ± 27au. Compared with Gd-BOPTA, SI was not different at 0.5 mmol/l (- 0.2%, P = 0.587) while it was higher (P < 0.001) at all other concentrations (range + 13.3%[4 mmol/l] - + 28.3%[1 mmol/l]). Regarding pipes without synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1275 ± 56au. Compared with Gd-BOPTA, SI was lower at 0.5 mmol/l (- 6.8%,P < 0.001), while it was higher (P < 0.001) at all other concentrations (range + 6.1%[4 mmol/l] - + 19.6% [1 mmol/l]). CONCLUSIONS: In vitro, Gd-BOPTA at 1 mmol/ had a + 28% SI increase in comparison to Gd-DTPA 2 mmol/l. SI similar to Gd-DTPA can be obtained using one fourth concentration of Gd-BOPTA.

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors.

Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure-activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.

Glutamate metabolism in cerebral mitochondria after ischemia and post-ischemic recovery during aging: relationships with brain energy metabolism.

Glutamate is involved in cerebral ischemic injury, but its role has not been completely clarified and studies are required to understand how to minimize its detrimental effects, contemporarily boosting the positive ones. In fact, glutamate is not only a neurotransmitter, but primarily a key metabolite for brain bioenergetics. Thus, we investigated the relationships between glutamate and brain energy metabolism in an in vivo model of complete cerebral ischemia of 15 min and during post-ischemic recovery after 1, 24, 48, 72, and 96 h in 1-year-old adult and 2-year-old aged rats. The maximum rates (Vmax ) of glutamate dehydrogenase (GlDH), glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were assayed in somatic mitochondria (FM) and in intra-synaptic 'Light' mitochondria and intra-synaptic 'Heavy' mitochondria ones purified from cerebral cortex, distinguishing post- and pre-synaptic compartments. During ischemia, none of the enzymes were modified in adult animals. In aged ones, glutamate-oxaloacetate transaminase was increased in FM and GlDH in intra-synaptic 'Heavy' mitochondria, stimulating glutamate catabolism. During post-ischemic recovery, FM did not show modifications at both ages while, in intra-synaptic mitochondria of adult animals, glutamate catabolism was increased after 1 h of recirculation and decreased after 48 and 72 h, whereas it remained decreased up to 96 h in aged rats. These results, with those previously published about Krebs' cycle and Electron Transport Chain (Villa et al., [2013] Neurochem. Int. 63, 765-781), demonstrate that: (i) Vmax of energy-linked enzymes are different in the various cerebral mitochondria, which (ii) respond differently to ischemia and post-ischemic recovery, also (iii) with respect to aging.

The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518-527).

Fertility preservation in women harboring deleterious BRCA mutations: ready for prime time?

Fertility issues have become critical in the management and counseling of BRCA mutation carriers. In this setting four points deserve consideration. (1) Women in general lose their ability to conceive at a mean age of 41 years, thus the suggested policy of prophylactic bilateral salpingo-oophorectomy at age 40 for BRCA mutation carriers does not affect the chances of natural pregnancy. Conversely, if the procedure is chosen at 35 years old, oocyte cryopreservation prior to surgery should be considered. (2) Some evidence suggests that ovarian reserve may actually be partly reduced in BRCA mutations carriers and that the mutation may affect ovarian responsiveness to stimulation. However, these findings are still controversial. (3) Breast cancer is not rare before the age of 40 and fertility preservation after diagnosis can be requested in a significant proportion of BRCA mutation carriers. Thus, a policy of oocyte cryopreservation in young healthy carriers deserves consideration. The procedure could be considered at a young age and in an elective setting, when ovarian stimulation may yield more oocytes of better quality. (4) Preimplantation genetic diagnosis (PGD) could be considered in BRCA mutations carriers, particularly when good quality oocytes have been stored at a young age. Based on the current knowledge, a univocal approach cannot be recommended; in depth patient counseling is warranted.