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Objective: To evaluate which early neurocognitive and behavioral precursors are associated with the development of attention-deficit/hyperactivity disorder (ADHD) and whether these are currently targeted in early interventions., Method: We conducted 2 systematic reviews and meta-analyses of empirical studies to examine the following: (1) early-life (0-5 years) neurocognitive and behavioral precursors associated with familial likelihood for ADHD, an early ADHD diagnosis/elevated ADHD symptoms, and/or the presence of later-childhood ADHD; and (2) interventions delivered to children aged 0 to 5 years targeting the identified precursors or measuring these as outcomes. Standardized mean differences (Hedges' g) and pre-post-treatment change scores (SMD) were computed., Results: A total of 149 studies (165,095 participants) investigating 8 neurocognitive and behavioral domains met inclusion criteria for part 1. Multi-level random-effects meta-analyses on 136 studies revealed significant associations between ADHD and poorer cognitive (g = -0.46 [95% CIs: -0.59, -0.33]), motor (g = -0.35 [CIs: -0.48, -0.21]) and language (g = -0.43 [CIs: -0.66, -0.19]) development, social (g = 0.23 [CIs: 0.03, 0.43]) and emotional (g = 0.46 [CIs: 0.33, 0.58]) difficulties, early regulatory (g = 0.30 [CIs: 0.18, 0.43]) and sleep (g = 0.29 [CIs: 0.14, 0.44]) problems, sensory atypicalities (g = 0.52 [CIs: 0.16, 0.88]), elevated activity levels (g = 0.54 [CIs: 0.37, 0.72]), and executive function difficulties (g = 0.34 [CIs: 0.05, 0.64] to -0.87 [CIs: -1.35, -0.40]). A total of 32 trials (28 randomized, 4 nonrandomized, 3,848 participants) testing early interventions that targeted the identified precursors met inclusion criteria for part 2. Multi-level random-effects meta-analyses on 22 studies revealed significant intervention-related improvements in ADHD symptoms (SMD = 0.43 [CIs: 0.22, 0.64]) and working memory (SMD = 0.37 [CIs: 0.06, 0.69])., Conclusion: Children aged 0 to 5 years with current or later-emerging ADHD are likely to experience difficulties in multiple neurocognitive/behavioral functions. Early interventions show some effectiveness in reducing ADHD symptoms, but their effects on neurocognitive/behavioral difficulties require further study., (Copyright © 2021 American Academy of Child & Adolescent Psychiatry. All rights reserved.)

The somatotropic axis, in addition to its well-known metabolic and endocrine effects, plays a pivotal role in modulation of inflammation. Moreover, growth hormone (GH)-releasing hormone (GHRH) has been involved in the development of various human tumors. In this work we aimed to investigate the consequences of GHRH deficiency on the development of inflammation-associated colon carcinogenesis in a mouse model of isolated GH deficiency due to generalized ablation of the GHRH gene [GHRH knock out (GHRHKO)]. Homozygous GHRHKO (-/-) male mice and wild type (C57/BL6, +/+) male mice as control group, were used. After azoxymetane (AOM)/dextran sodium sulfate (DSS) treatment -/- mice displayed higher Disease Activity Index (DAI) score, and more marked weight loss compared to +/+ animals. Additionally, -/- mice showed a significant increase in total tumors, in particular of large size predominantly localized in distal colon. In colonic tissue of AOM/DSS-treated -/- mice we found the presence of invasive adenocarcinomas, dysplasia and colitis with mucosal ulceration. Conversely, AOM/DSS-treated +/+ mice showed only presence of adenomas, without invasion of sub-mucosa. Treatment with AOM/DSS significantly increased prostaglandin (PG)E 2 and 8-iso-PGF 2α levels along with cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, nuclear factor kappa B (NF-kB) and inducible nitric oxide synthase (iNOS) gene expression, in colon specimens. The degree of increase of all these parameters was more markedly in -/- than +/+ mice. In conclusion, generalized GHRH ablation increases colon carcinogenesis responsiveness in male mice. Whether this results from lack of GH or GHRH remains to be established., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To compare brainstem acoustic evoked potentials (BAEP) and magnetic resonance imaging (MRI) in the differential diagnosis of intracranial hypotension (IH), Chiari malformation (CM) and sensorineural hearing loss (SNHL)., Methods: BAEP were recorded in 18 IH, 18 CM, 20 SNHL patients and 52 controls. MRI were acquired in all IH and CM patients., Results: Abnormal BAEP were observed in 94% of IH patients, in 33% of CM and 70% of SNHL patients. After recovery from IH, BAEP abnormalities disappeared. Internal auditory canal (IAC) MRI abnormalities were described in 88% of IH patients. MRI signs of IH were observed in 33-78% in IH patients, but the most frequent MRI sign was 8th nerve T2 hyperintensity, with contrast enhancement in T1 sequences. This finding, combined with wave I latency, yielded highest specificity and sensitivity for IH diagnosis., Conclusions: Our study points out how IH can be effectively distinguished from CM and SNHL through the contribution of neurophysiology and MRI; in particular, evaluation of the 8th nerve achieves a high sensitivity and specificity in patients with IH. Further studies are required to examine the combined use of BAEP recordings ad MRI in diagnosis and monitoring of patients affected by IH., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Palatability and variety of foods are major reasons for hedonic eating, and hence for obesity. Hemopressin, a hemoglobin α chain-derived peptide, plays antagonist/inverse agonist role on cannabinoid (CB)1 receptors, while RVD-hemopressin(α)[RVD-hp(α)], a N-terminally extended form of hemopressin, has been reported as an allosteric modulator of CB1 and CB2 receptors. We investigated the effects of 14 daily intraperitoneal injections of RVD-hp(α), in Sprague-Dawley rats fed a highly palatable cafeteria-style (CAF) diet (30% fat, 56% carbohydrate, 14% protein; 4.20 kcal/g) compared to standard laboratory chow (STD) food (3.5% fat, 63% carbohydrate, 14% protein, 19.5% other components without caloric value; 3.20 kcal). Food intake, body weight and locomotor activity were recorded throughout the study. Finally, rats were sacrificed and agouti-related peptide (AgRP), neuropeptide Y (NPY), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and fatty acid amide hydrolase (FAAH) gene expression in the hypothalamus was measured by real-time reverse transcription polymerase chain reaction. We found that CAF diet increased food intake as compared to STD diet. In both STD and CAF diet fed rats, RVD-hp(α) treatment inhibited food intake, increased locomotor activity but did not modify body weight. In vehicle injected animals, CAF as compared to STD diet increased AgRP gene expression. RVD-hp(α) treatment decreased POMC mRNA levels in both diet groups and lowered the elevated AgRP levels induced by CAF diet. RVD-hp(α) treatment plays an anorexigenic role paralleled by increased locomotor activity both in STD and CAF diet fed rats. The inhibition of feeding could be partially mediated by lowering of hypothalamic POMC and AgRP gene expression levels., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Impairment of growth hormone (GH) signaling has been associated with increased feeding and adiposity. The gastric hormone ghrelin, in addition to its GH-secretagogue effects, stimulates food intake after both central and peripheral administration. In the present study we further investigated the feeding regulatory role of the ghrelin-GH axis in a mouse model of isolated GH deficiency due to targeted ablation of the GH-releasing hormone (GHRH) gene [GHRH knockout (GHRHKO)]. We evaluated the effects of intracerebroventricular ghrelin administration on feeding behavior, related hypothalamic neuropeptides and neurotransmitters, and serum ghrelin levels in mice homozygous for GHRHKO allele (-/-) and heterozygous (+/-) control animals. Vehicle-treated GHRHKO mice showed increased food intake compared to heterozygotes, associated with increased circulating ghrelin levels. Moreover, -/- mice showed elevated hypothalamic levels of neuropeptide Y (NPY), agouti-related peptide (AgRP) mRNAs and norepinephrine (NE) and decreased corticotropin-releasing hormone (CRH) mRNA levels. Ghrelin treatment significantly augmented food intake in both genotypes, but the relative increase compared to vehicle-treated animals was higher in -/- than +/- mice. In the hypothalamus, ghrelin increased AgRP and decreased CRH gene expression only in heterozygous mice, while it induced a significant reduction in proopiomelanocortin (POMC) mRNA levels in -/- mice. Ghrelin treatment also decreased hypothalamic serotonin (5-hydroxytriptamine, 5-HT) and dopamine (DA) levels in both genotypes. Additionally, we observed increased DA metabolism induced by ghrelin in both genotypes. In conclusion, dysregulation of the ghrelin-GHRH-GH axis in GHRHKO mice could lead to increased feeding secondary to elevated circulating levels of ghrelin, and the obesogenic phenotype is likely mediated by elevated NPY and AgRP, and decreased CRH gene expression in the hypothalamus., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Growth hormone (GH) deficiency (GHD) leads to growth failure and changes in body composition, including increased fat accumulation and reduced lean body mass in both humans and rodents. The aim of this study was to examine the factors that contribute to energy imbalance in the GH releasing hormone knock out (GHRHKO) mice, a well established model of GHD., Design: We evaluated food intake (of standard laboratory chow), total body weight (TBW), locomotor activity, body temperature and interscapular brown adipose tissue (BAT) weight in 8 adult male mice homozygous for the GHRHKO allele (-/-) and 8 heterozygous (+/-) animals as controls. The gene expression of uncoupling protein-1 (UCP-1) in BAT and the levels of norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine, 5-HT) in the ventral striatum were measured by real-time reverse transcription polymerase chain reaction (RT-PCR) and high performance liquid chromatography (HPLC) analysis, respectively., Results: Throughout 2 months of observation -/- mice consumed approximately 40% more food (normalized to TBW; P<0.001), and showed increased locomotor activity in 24h time compared to controls (P<0.05). Moreover, -/- animals showed increased body temperature (P<0.001), BAT weight (P<0.001), and UCP-1 gene expression (P<0.001), while NE levels in the striatum area were lower (P<0.05) than controls., Conclusions: The present study demonstrates that the increased food intake observed in GHRH ablated animals is associated with increased locomotor and thermogenic activity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: GH-releasing hormone (GHRH) is a key regulator of GH secretion. The role of GH in anxiety is somewhat contradictory. The aim of this study is to elucidate the consequences of lack of GHRH on emotional behaviour in a mouse model of GH deficiency due to removal of the GHRH gene (GHRH knock out, GHRHKO)., Design: Homozygous GHRHKO and wild type male mice were utilized for this study. The emotional behaviour was measured through a battery of behavioural tests (locomotor activity/open field, light-dark exploration, elevated plus maze, forced swim test, tail suspension test). To correlate the emotional behaviour with brain neurochemistry, we evaluated thyrotropin-releasing hormone (TRH) gene expression in hypothalamic tissue by real-time PCR, and the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) in prefrontal cortex by HPLC analysis., Results: GHRHKO mice showed increased exploratory activity. In the open field test (P<0.005), light-dark box (P<0.005) and elevated plus maze (P<0.05), GHRHKO mice demonstrated a decrease in anxiety-related behaviour. In addition, GHRHKO mice showed reduced immobility time with respect to control in forced swim test and tail suspension test (P<0.0001). The gene expression of hypothalamic TRH (P<0.05) was increased, while NE levels in prefrontal cortex were decreased compared to control (P<0.05)., Conclusion: These results suggest that in male mice GHRH deficiency brings about an increased physical activity and decreased anxiety- and depression-related behaviour, possibly related to increased TRH and decreased NE levels in the brain., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Ca2+ sparks are localized intracellular Ca2+ release events from the sarcoplasmic reticulum in muscle cells that result from synchronized opening of ryanodine receptors (RyR). In mammalian skeletal muscle, RyR1 is the predominant isoform present in adult skeletal fibers, while some RyR3 is expressed during development. Functional studies have revealed a differential role for RyR1 and RyR3 in the overall Ca2+ signaling in skeletal muscle, but the contribution of these two isoforms to Ca2+ sparks in adult mammalian skeletal muscle has not been fully examined. When enzyme-disassociated, individual adult skeletal muscle fibers are exposed to an osmotic shock, the resting fiber converts from a quiescent to a highly active Ca2+ release state where Ca2+ sparks appear proximal to the sarcolemmal membrane. These osmotic shock-induced Ca2+ sparks occur in ryr3(-/-) muscle with a spatial distribution similar to that seen in wild type muscle. Kinetic analysis reveals that systemic ablation of RyR3 results in significant changes to the initiation, duration and amplitude of individual Ca2+ sparks in muscle fibers. These changes may reflect the adaptation of the muscle Ca2+ signaling or contractile machinery due to the loss of RyR3 expression in distal tissues, as biochemical assays identify significant changes in expression of myosin heavy chain protein in ryr3(-/-) muscle.

There is compelling evidence that combinations of antiretroviral drugs are significantly more effective than monotherapy and appear, at least in the short run, to offset problems caused by the rapid emergence of drug resistance which is characteristic of human immunodeficiency virus (HIV) infection.1,2 The routine prescribing of combination antiretroviral therapy appears to have contributed to a fall in HIV-related in-patient admissions, mortality and morbidity, with a concomitant increase in pharmacy costs. In this paper we have attempted to determine to what extent the reduction in direct hospital costs (reduced in-patient admissions, diagnostic tests and management of complications) will offset the considerably increased pharmacy costs; by using Markhov modelling procedures together with locally gathered costs data.

The objective of the study was to establish the relationship between the results of positive and abnormal cervical smears and the corresponding colposcopic biopsy results and its relevance to clinical management. A retrospective analysis of linked results was carried out at the Princess Anne Hospital, Southampton. The main outcome measure was the correspondence between a positive or abnormal cervical smear and the related colposcopic biopsy. Colposcopic biopsies were carried out on 1,841 consecutive women. Of these, 1,424 (77.4%) had moderate or severe dyskaryosis on their smears. Of the 1,767 with definitive results on their smear, 1,101 (62%) showed exact correspondence between the cervical smear and the colposcopic biopsy. Ninety-one (26%) of all women with mildly dyskaryotic smears were reported as showing CIN II or CIN III on biopsy. We conclude that women with moderate or severe changes on cervical smear should not be asked to attend for confirmatory colposcopic biopsy prior to treatment, but those with persistent mild changes should be referred for separate diagnostic colposcopy.