High frame-rate contrast enhanced ultrasound (HIFR-CEUS) in the characterization of small hepatic lesions in cirrhotic patients.

BACKGROUND: To show the effectiveness of plane wave HighFrame-Rate CEUS (HiFR-CEUS) compared with "conventional" (plane wave) CEUS (C-CEUS) in the characterization of small (< 2 cm) focal liver lesions (FLLs) not easily detected by CT in cirrhotic patients. HiFR-CEUS exploit an ultra-wideband nonlinear process to combine fundamental, second and higher-order harmonic signals generated by ultrasound contrast agents to increase the frame rate. C-CEUS is limited by the transmission principle, and its frame-rate is around 10 FPS. With HiFR-CEUS (Shenzhen Mindray Bio-Medical Electronics Co., China), the frame-rate reached 60 FPS. MATERIAL AND METHODS: Ultrasound detected small FLLs (< 2 cm) in 63 cirrhotic patients during follow-up (June 2019-February 2020); (7 nodules < 1 cm and were not evaluable by spiral CT). Final diagnosis was obtained with MRI (47) or fine needle aspiration (16 cases) C-CEUS was performed and HiFR-CEUS was repeated after 5 min; 0.8-1.2 ml of contrast media (SonoVue, Bracco, Italy) was used. 57 nodules were better evaluable with HiFR-CEUS; 6 nodules were equally evaluable by both techniques; final diagnosis was: 44 benign lesions (29 hemangiomas, 1 amartoma, 2 hepatic cysts; 2 focal nodular hyperplasias, 3 regenerative macronodules, 3 AV-shunts, 3 hepatic sparing areas and 1 focal steatosis) and 19 malignant one (17 HCCs, 1 cholangioca, 1 metastasis); statistical evaluation for better diagnosis with X2 test (SPSS vers. 26); we used LI-RADS classification for evaluating sensitivity, specificity PPV, NPV and diagnostic accuracy of C- and HFR-CEUS. Corrispective AU-ROC were calculated. RESULTS: C-CEUS and HiFR-CEUS reached the same diagnosis in 29 nodules (13 nodules > 1 < 1.5 cm; 16 nodules > 1.5 < 2 cm); HiFR-CEUS reached a correct diagnosis in 32 nodules where C-CEUS was not diagnostic (6 nodules < 1 cm; 17 nodules > 1 < 1.5 cm; 9 nodules > 1.5 < 2 cm); C-CEUS was better in 2 nodules (1 < 1 cm and 1 > 1 < 1.5 cm). Some patient's (sex, BMI, age) and nodule's characteristics (liver segment, type of diagnosis, nodule's dimensions (p = 0.65)) were not correlated with better diagnosis (p ns); only better visualization (p 0.004) was correlated; C-CEUS obtained the following LI-RADS: type-1: 18 Nodules, type-2: 21; type-3: 7, type-4: 7; type-5: 8; type-M: 2; HiFR-CEUS: type-1: 38 Nodules, type-2: 2; type-3:4, type-4: 2; type-5: 15; type-M: 2; In comparison with final diagnosis: C-CEUS: TP: 17; TN: 39; FP: 5; FN:2; HIFR-CEUS: TP: 18; TN: 41; FP: 3; FN:1; C-CEUS: sens: 89.5%; Spec: 88.6%, PPV: 77.3%; NPV: 95.1%; Diagn Acc: 88.6% (AU-ROC: 0.994 ± SEAUC: 0.127; CI: 0.969-1.019); HiHFR CEUS: sens: 94.7%; Spec: 93.2%, PPV: 85.7%; NPV: 97.6%; Diagn Acc: 93.2% (AU-ROC: 0.9958 ± SEAUC: 0.106; CI: 0.975-1.017) FLL vascularization in the arterial phase was more visible with HiFR-CEUS than with C-CEUS, capturing the perfusion details in the arterial phase due to a better temporal resolution. With a better temporal resolution, the late phase could be evaluated longer with HiFR-CEUS (4 min C-CEUS vs. 5 min HiFR-CEUS). CONCLUSION: Both C-CEUS and HIFR-CEUS are good non invasive imaging system for the characterization of small lesions detected during follow up of cirrhotic patients. HiFR-CEUS allowed better FLL characterization in cirrhotic patients with better temporal and spatial resolution capturing the perfusion details that cannot be easily observed with C-CEUS.

Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone.

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that alpha-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features.

Normal CSF oxytocin and NPY levels in OCD.

BACKGROUND: Attention has recently been focused on central nervous system neuropeptides as potential mediators of the symptom profile of obsessive-compulsive disorder (OCD). Increased CSF levels of the anxiolytic neuropeptide oxytocin have been reported in OCD. CSF levels of NPY, another anxiolytic neuropeptide, have not been studied. METHODS: We measured CSF oxytocin and NPY in 14 OCD patients and 26 healthy normal volunteers. RESULTS: There were no significant differences between the OCD patients and control subjects in CSF oxytocin or NPY levels. In both the OCD and control groups, women had significantly higher CSF oxytocin levels than men. CONCLUSIONS: These results do not support a prior finding of elevated CSF oxytocin in OCD patients and do not provide any evidence for an abnormality of NPY regulation in OCD.

Alpha 2 adrenergic agonists. Neurochemistry, efficacy, and clinical guidelines for use in children.

The alpha 2 adrenergic agonists are used to treat a variety of psychiatric disorders and their usage has been increasing. This article presents the rationale and neurochemical basis for treatment of psychiatric disorders with alpha 2 agents, reviews studies examining clinical efficacy, and develops guidelines for usage. Case vignettes are presented to illustrate how the alpha 2 agents can successfully be used in practice.

Response to oCRH in depressed and nondepressed adolescents: does gender make a difference?

OBJECTIVE: To examine the hypothesis that hypothalamic-pituitary-adrenal responses to stress vary across gender, contributing to gender differences in the prevalence of depression. METHOD: This study examined gender differences between depressed (n = 21) and control (n = 20) adolescents in adrenocorticotropic hormone (ACTH) and cortisol response to two ovine corticotropin-releasing hormone (oCRH) tests, at baseline and following a cognitive stressor. RESULTS: Boys had higher (p < .05) measures of ACTH than girls, regardless of depression status, whereas corresponding cortisol parameters were similar in both groups. Cortisol measures were higher (p < .05) at time 1 than at time 2 in both groups, a phenomenon that might reflect the novelty of the situation. CONCLUSIONS: Gender differences in hormone responses may be related to differences in peripheral metabolism of ACTH, resulting in changes of immunoreactivity but not bioactivity or a different set point of the hypothalamic-pituitary-adrenal axis. The pattern of ACTH and cortisol responses to oCRH and the 24-hour excretion of free cortisol was normal in adolescents with depression, probably reflecting normal negative feedback mechanisms at this age or that most of these patients suffer from atypical rather than melancholic depression.

Diurnal variation of cerebrospinal fluid immunoreactive corticotropin-releasing hormone levels in healthy volunteers.

CRH is not only secreted into hypophyseal protal blood where it is believed to regulate the circadian rhythm of pituitary-adrenal activity, but is also measurable in cerebrospinal fluid (CSF). Altered CSF immunoreactive CRH (IR-CRH) levels have been found in patients with a number of neuropsychiatric disorders and have been implicated in some of the symptoms of these disorders. To further study the potential functional relevance of CRH in human CSF, we examined whether a nonuniform temporal pattern of IR-CRH levels existed in CSF using hourly sampling over a 30-h period in six healthy volunteers. CSF was withdrawn continuously at 6 mL/h through a catheter placed in the lumbar subarachnoid space and connected to a miniroller pump and fraction collector. A significant diurnal variation in CSF IR-CRH levels was observed (P < 0.001), with highest levels between 1830-2330 h and lowest levels around 0730 h. This pattern was nearly opposite that of plasma cortisol levels, which showed the expected peak around 0800 h and nadir around 2000-2200 h. In addition, CSF IR-CRH levels in three of the six volunteers showed significant negative correlations with simultaneous plasma cortisol levels. These data suggest that CSF IR-CRH concentrations are negatively modulated by peripheral cortisol secretion, which may be one factor involved in the entrainment of this rhythm. Although the functional significance of this diurnal variation in CSF IR-CRH levels is unknown, the presence of a distinct temporal organization of CRH release into the CSF in humans is compatible with the idea that CSF may play a functional role in or otherwise reflect nonsynaptic information processing in the central nervous system. Diurnal factors should be taken into account in future studies of CRH concentrations in human CSF.

Facilitation of cocaine kindling by glucocorticoids in rats.

We report that glucocorticoids significantly facilitated the development of cocaine-induced kindled seizures. These results suggest that glucocorticoids may have effects on the development of kindled seizures which are similar to those of the neuropeptide, corticotropin-releasing hormone (CRH), with which they show a close functional relationship. These results may be of interest in the light of data showing that glucocorticoids increase CRH expression in the central nucleus of the amygdala, which is an important site for the development of kindling.

Effects of the glucocorticoid antagonist RU 486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers: enhancement of plasma ACTH and cortisol secretion in underweight patients.

To further explore whether the hypercortisolism of anorexia nervosa reflects an alteration in the set point for corticotropin-releasing hormone (CRH) secretion or is a manifestation of glucocorticoid resistance, we examined plasma ACTH and cortisol responses to the competitive glucocorticoid antagonist RU 486 (10 mg/kg, p.o. at 8.00 h) versus placebo (PBO) in 7 healthy female volunteers and 8 patients with DSM-III-R anorexia nervosa, all of whom were studied while underweight [64.3 +/- 2.1% average body weight (ABW), mean +/- SE] and 5 of whom were restudied longitudinally following refeeding (> or = 85% ABW, mean 87.4 +/- 0.4% ABW). Blood samples were obtained from 16.00 to 16.30 h and from 4.00 to 8.00 h following dosing. Underweight anorexics were significantly hypercortisolemic by 24 h urinary free cortisol excretion compared with controls (239 +/- 37 vs. 119 +/- 12 nmol/day, p < 0.01). Both controls and underweight anorexics had robust early morning (4.00-8.00 h) plasma cortisol responses to RU 486 (465 +/- 61 and 719 +/- 49 nmol/l) compared with PBO (370 +/- 52 and 451 +/- 31 nmol/l; p < 0.02 and p < 0.01, respectively). The underweight anorexics showed a significant mean early morning plasma ACTH response to RU compared with placebo (3.28 +/- 0.63 vs. 2.01 +/- 0.24 pmol/l, p < 0.05), while the controls showed a trend toward an increase in mean plasma ACTH after RU (3.11 +/- 0.36 pmol/l) compared with PBO (2.31 +/- 0.41 pmol/l, p < 0.13); plasma ACTH means were greater on the RU day than the placebo day at 20 of 25 sampling points (p < 0.001). However, the increment in ACTH on the RU day compared to the placebo day was greater in the underweight anorexics at the first 20 of 25 consecutive time points of the early morning sampling period (p < 0.001). Moreover, underweight anorexics showed a significant plasma ACTH and cortisol response to RU 486 at 16.00-16.30 h (8-8.5 h following administration), while the controls showed no significant response of plasma ACTH or cortisol at this time. When restudied following weight recovery, anorexic patients showed reductions in 24-hour urinary free cortisol excretion (to 191 +/- 40 nmol/day) which were no longer significantly elevated compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)

Clonidine-induced feeding: analysis of central sites of action and fiber projections mediating this response.

Clonidine (CLON), an alpha-adrenergic agonist, was used in conjunction with norepinephrine (NE) to elicit feeding in satiated rats that had sustained hypothalamic electrolytic lesions, or coronal knife cuts at the hypothalamic, midbrain or pontine level of the brainstem. Electrolytic lesions of the paraventricular nucleus (PVN) of the hypothalamus significantly attenuated feeding normally stimulated by intraperitoneal injection of CLON. This contrasts with lesions in the dorsomedial or perifornical hypothalamic regions which had no effect on CLON-elicited eating. Knife cuts placed in the posterior hypothalamus and throughout the midbrain tegmentum also left intact the CLON eating response, in contrast to specific cuts in the dorsal pontine tegmentum which disrupted feeding elicited by PVN injections of NE and CLON, as well as by peripheral administration of CLON. Analyzed together, these results with effective and ineffective cuts relative to CLON and NE feeding provide evidence for an alpha-adrenergic feeding circuit which originates in the PVN and descends from this nucleus, via a dorsal periventricular course, through the diencephalon and midbrain. Further caudally, these fibers mediating NE and CLON feeding then appear to traverse ventrolaterally into the dorsolateral pontine tegmentum on their way to the dorsal medulla.