Pharmacological characterisation of [(pX)Phe4]nociceptin(1-13)NH2 analogues. 2. In vivo studies

As part of a structure-activity study focused on the Phe(4) residue of nociceptin (NC) (1-13)NH(2), we identified two highly potent and selective agonists for the OP(4) receptor, [(pF)Phe(4)]NC(1-13)NH(2) and [(pNO(2))Phe(4)]NC(1-13)NH(2), whose in vitro pharmacological profiles have been described in the companion paper. In the present study, we investigated the actions of [(pF)Phe(4)]NC(1-13)NH(2) and compared it with those of NC(1-13)NH(2) in a battery of vivo assays.In the locomotor activity test in mice, 1 nmol NC(1-13)NH(2) given intracerebroventricularly (i.c.v.) caused a significant decrease (about 70% inhibition) in activity for the first 15 min following injection; [(pF)Phe(4)]NC(1-13)NH(2), at the same dose, exerted a similar inhibitory effect that continued until the end of the observation period (30 min). This effect was prevented by the selective OP(4) receptor antagonist [Nphe(1)]NC(1-13)NH(2) (10 nmol, i.c.v.). In the tail-withdrawal assay in mice, [(pF)Phe(4)]NC(1-13)NH(2) mimicked the effects of NC(1-13)NH(2) producing pronociceptive and antimorphine effects following i.c.v. administration. In both experimental paradigms, the actions of [(pF)Phe(4)]NC(1-13)NH(2) were longer lasting (>60 min) compared to those of NC(1-13)NH(2) (ca. 30 min). In unanaesthetised normotensive mice, bolus intravenous (i.v.) injection of 100 nmol/kg of [(pF)Phe(4)]NC(1-13)NH(2) decreased mean blood pressure and heart rate; these effects were longer lasting than those elicited by the same dose of NC(1-13)NH(2). I.c.v. administration of [(pF)Phe(4)]NC(1-13)NH(2) dose-dependently stimulated feeding in rats, and was about tenfold more potent than NC(1-13)NH(2).Collectively, the present data demonstrate that, in a variety of in vivo assays, NC(1-13)NH(2) and [(pF)Phe(4)]NC(1-13)NH(2) mimicked the actions of NC. [(pF)Phe(4)]NC(1-13)NH(2) was more potent and its in vivo effects were longer lasting than those of NC(1-13)NH(2) and NC.     

Polyunsaturated fatty acids mapping by (1)H MR-chemical shift imaging.

Parametric mapping of polyunsaturated fatty acids (PUFA) distribution in adipose tissues was obtained by (1)H chemical shift imaging (CSI). A matrix of spectra, acquired with a CSI sequence having two spatial and one spectroscopic dimension, was processed with ad hoc algorithms. The protocol was applied to phantoms containing different lipids in which the degree of polyunsaturation was determined by high-resolution nuclear magnetic resonance (NMR). High correlation (R(2) = 0.998) between degrees of polyunsaturation given by our protocol and that measured by high-resolution NMR was found. The thoracic region of rats was also examined. Parametric maps of the polyunsaturation degree were obtained for the brown adipose tissue and the white axillary fat: the first deposit was found more polyunsaturated than the second. Finally, in vivo mapping of the inguinal region of the rat was produced that allowed us to individuate PUFA-rich areas in adipose tissue. This work demonstrates the feasibility of PUFA imaging in vivo.     

Scintigraphic patterns of adrenocortical carcinoma: morpho-functional correlates.

OBJECTIVE: Adrenocortical scintigraphy has demonstrated clinical utility in the morpho-functional characterization of adrenal tumors. The aim of this study was to identify possible relationships between the scintigraphic pattern and endocrine and/or morphological data in a series of adrenocortical carcinomas. DESIGN AND METHODS: Twenty-one patients with adrenocortical carcinoma (11 nonfunctioning and 10 hormone-secreting) were investigated with 75Se-methyl-nor-cholesterol scintigraphy. Clinical, hormonal, radiological, and pathological data were analyzed. RESULTS: The adrenal mass showed no radiocholesterol uptake in 18 cases (11 nonfunctioning and 7 functioning lesions). Contralateral normal adrenal gland was visualized in all patients with nonfunctioning tumors, whereas classic bilateral nonvisualization was observed in the 7 cases with hyperfunctioning masses. Three patients with cortisol-producing carcinomas showed radiotracer uptake by the mass, without visualization of the contralateral gland. At histology, the tumors were shown to be undifferentiated adrenocortical carcinomas; they had an aggressive clinical behavior. CONCLUSIONS: Radiocholesterol scintigraphy has an important role in diagnosing adrenocortical carcinomas, which typically are not visualized. However, 30% of hypersecreting adrenocortical carcinomas show an atypical increased tracer uptake, not predictive of the biochemical and histological features of the tumor.     

Non-invasive pressure support ventilation in severe community-acquired pneumonia

OBJECTIVE: To explore three aspects of non-invasive pressure support ventilation (NIPSV) applied by face mask to patients with acute respiratory failure (ARF) due to severe community-acquired pneumonia (CAP): (1) the initial acute effects on respiratory rate, gas exchange and hemodynamics, (2) the clinical course and outcome during ICU and hospital stay, (3) the nursing workload as measured by the daily PRN 87 (Project Research in Nursing) score. SETTING: Medical ICU, University Hospital. DESIGN: Prospective, observational study. PATIENTS: Patients without any prior history of chronic lung disease, consecutively admitted to the ICU to receive NIPSV for ARF due to severe CAP. MEASUREMENTS AND RESULTS: (means +/- SD): Twenty-four patients aged 49+/-17 years, admission APACHE II 13+/-5, were included. Admission PaO2/FIO2, alveolar-arterial oxygen difference (DA-aO2) and PaCO2 were 104+/-48, 447+/-120 and 40+/-10 mmHg, respectively. All patients were normotensive. During the initial NIPSV trial respiratory rate decreased from 34+/-8 to 28+/-10 breaths/min (p < 0.001) and arterial oxygenation improved (PaO2/FIO2 104+/-48 vs 153+/-49, DA-aO2 447+/-120 vs 370+/-180 mmHg, p < 0.001) while PaCO2 remained unchanged. There were no hemodynamic effects. Subsequently, a total of 133 NIPSV trials were performed (median duration 55 min, range 30-540 min) over 1-7 days. No complication occurred during NIPSV. Sixteen patients were intubated (66%) 1.3+/-1 days after inclusion. Upon inclusion, the patients who were subsequently intubated were older (55+/-15 vs 37+/-12 years) and more severely hypoxemic (63+/-11 vs 80+/-15 mmHg, p < 0.05) than those not requiring intubation. Eight patients died (33 %), all in the intubated group. Median lengths of stay in the ICU and hospital were longer in intubated patients (ICU 16 days, range 3-64 vs 6 days, range 3-7, p < 0.05; hospital 23 days, range 9-77 vs 9.5 days, range 4-42, p < 0.05). Mean daily total PRN points were stable throughout the NIPSV period and were not different between the groups. Only 14% of PRN points resulted from respiratory therapy interventions. PRN score was higher during the first 24 h following intubation than during the first 24 h of NIPSV (278+/-55 vs 228+/-24 points, p < 0.05). CONCLUSION: Despite initial improvement in arterial oxygenation with NIPSV in patients with ARF due to severe CAP, the intubation rate is high. However, the more favorable outcome and shorter ICU and hospital stays when intubation is avoided, as well as the short delay required to assess the success or failure of NIPSV warrants a trial of NIPSV in this setting. The nursing workload remains stable during NIPSV and does not result predominantly from respiratory therapy interventions.     

The role of prenatal and perinatal factors in eating disorders: a systematic review

Numerous studies showed that factors influencing fetal development and neonatal period could lead to lasting alterations in the brain of the offspring, in turn increasing the risk for eating disorders (EDs). This work aims to systematically and critically review the literature on the association of prenatal and perinatal factors with the onset of EDs in the offspring, updating previous findings and focusing on anorexia nervosa (AN) and bulimia nervosa (BN). A systematic literature search was performed on Pubmed, PsycINFO, and Scopus. The drafting of this systematic review was conducted following the PRISMA statement criteria and the methodological quality of each study was assessed by the MMAT 2018. A total of 37 studies were included in this review. The factors that showed a more robust association with AN were higher maternal age, preeclampsia and eclampsia, multiparity, hypoxic complications, prematurity, or being born preterm (< 32 weeks) and small for gestational age or lower birth size. BN was only associated with maternal stress during pregnancy. Many methodological flaws emerged in the considered studies, so further research is needed to clarify these inconsistencies. Altogether, data are suggestive of an association between prenatal and perinatal factors and the onset of EDs in the offspring. Nevertheless, given the methodological quality of the available literature, firm conclusions cannot be drawn and whether this vulnerability is specific to EDs or mental disorders remains to be defined. Also, a strong need for longitudinal and well-designed studies on this topic emerged.

     

Mini-invasive videoassisted thyroid lobectomy for neonatal hyperfunctioning adenoma related to a somatic TSHr gene mutation

We report here a case of a paediatric hyperthyroidism due to a micro-macro-follicular thyroid adenoma in the presence of heterozygous point mutation of TSH receptor (TSHr). We describe the case from the initial diagnosis, through laboratoristic examinations and imaging techniques, until the radical surgical treatment made by a mini-cervicotomic videoassisted technique. We also explained the genetic work-up from peripheral blood and thyroid adenoma tissue.     

In situ proliferation contributes to accumulation of tumor‐associated macrophages in spontaneous mammary tumors

Infiltration of a neoplasm with tumor‐associated macrophages (TAMs) is considered an important negative prognostic factor and is functionally associated with tumor vascularization, accelerated growth, and dissemination. However, the ontogeny and differentiation pathways of TAMs are only incompletely characterized. Here, we report that intense local proliferation of fully differentiated macrophages rather than low‐pace recruitment of blood‐borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified. We propose that, akin to various MU subtypes in nonmalignant tissues, local proliferation and CSF1 play a vital role in the homeostasis of TAMs.