An update on pharmacotherapy of autism spectrum disorder in children and adolescents.

To date, no medication is proven to be effective in treating core symptoms of autism spectrum disorder (ASD). Psychotropic medications are widely used to target emotional and behavioural symptoms in ASD. This article reviewed evidence for pharmacotherapy, novel therapeutic agents, and Complementary and Alternative Medicine (CAM) in children and adolescents with ASD. Currently, only risperidone and aripiprazole have been approved by the US Food and Drug Administration (FDA) for treatment of irritability associated with ASD in children and adolescents. However, associated metabolic side-effects are concerning. Evidence supports use of methylphenidate and atomoxetine for attention deficit hyperactivity disorder (ADHD) symptoms and clonidine and guanfacine ER appear to be helpful. SSRIs are poorly tolerated and lack evidence in reducing restricted repetitive behaviours (RRB), anxiety, and depression. Buspirone shows promise in the treatment of RRB. The evidence is inconsistent for the effectiveness of anti-epileptic medications. Recent studies of glutamatergic, Gamma-aminobutyric acid (GABA)ergic, and cholinergic agents and oxytocin show inconsistent results. Despite wide use of CAM agents, the evidence is inconclusive. Melatonin can be helpful in reducing sleep problems. Overall, the evidence is limited for pharmacotherapy in children with ASD, and side-effects with long-term use can be burdensome.

Pharmacotherapy for mental health problems in people with intellectual disability.

PURPOSE OF REVIEW: Psychotropic medications are commonly prescribed to people with intellectual disability. We reviewed current evidence-based pharmacotherapy options and recent updates to guide clinicians in their medication management plans. RECENT FINDINGS: Antipsychotics, particularly risperidone, appear to be effective in reducing problem behaviors in children with intellectual disability. Evidence in adults is inconclusive. Methylphenidate appears to be effective, and α-agonists appear promising in reducing attention-deficit hyperactivity disorder symptoms. Lithium might be effective in reducing aggression. Evidence is limited to support the use of antiepileptic drugs, anxiolytics, and naltrexone for management of problem behaviors. Antidepressants may be poorly tolerated and might not be effective in reducing repetitive/stereotypic behaviors.In recent trials, glutamatergic and GABAergic agents for fragile X syndrome, and acetylcholinesterase inhibitors for Down's syndrome, failed to show efficacy. Growth hormone treatment might improve cognition and behavior in Prader-Willi syndrome population. Results from oxytocin trials on social behaviors are inconclusive albeit promising. Melatonin appears to improve sleep. Most trials of dietary supplements did not show benefits. SUMMARY: Evidence-based pharmacotherapy options in people with intellectual disability are limited, and many agents can cause substantial adverse events. For this reason, clinicians should consider pharmacotherapy as only a part of comprehensive treatment, and regularly assess drug effects, adverse events, and the feasibility of decreasing dose or withdrawing medications.

An update on pharmacotherapy for autism spectrum disorder in children and adolescents.

PURPOSE OF REVIEW: Although there is no known efficacious pharmacotherapy for core symptoms of autism spectrum disorder (ASD), psychotropic medications are commonly prescribed for behavioral/emotional symptoms associated with ASD. We reviewed current evidence-based pharmacotherapy options and updates from recent noteworthy studies. RECENT FINDINGS: Atypical antipsychotics, particularly risperidone and aripiprazole, are effective in reducing irritability, stereotypy and hyperactivity. Metabolic adverse events, including weight gain and dyslipidemia, are common. Methylphenidate is effective in reducing attention-deficit hyperactivity disorder (ADHD) symptoms. Atomoxetine and alpha-2 agonists appear effective in reducing ADHD symptoms. Selective serotonin reuptake inhibitors are not effective in improving repetitive behaviors in children with ASD, and frequently cause activating adverse events. Efficacy of antiepileptic drugs is inconclusive. Overall, efficacy and tolerability of pharmacotherapy in children with ASD are less favorable than data seen in typically developing children with similar symptoms. Newer agents, including glutamatergic agents and oxytocin, appear promising albeit with mixed results. SUMMARY: Current evidence-based pharmacotherapy options in children with ASD are very limited, and many have substantial adverse events. Clinicians should use pharmacotherapy as a part of comprehensive treatment, and judiciously weigh risks and benefits. New pharmacotherapy options for core symptoms as well as co-occurring symptoms of ASD are in urgent need.

ESM-1 regulates cell growth and metastatic process through activation of NF-κB in colorectal cancer.

In our previous study, we reported that endothelial cell specific molecule-1 (ESM-1) was increased in tissue and serum from colorectal cancer patients and suggested that ESM-1 can be used as a potential serum marker for early detection of colorectal cancer. The aim of this study was to evaluate the role of ESM-1 as an intracellular molecule in colorectal cancer. ESM-1 expression was knocked down by small interfering RNA (siRNA) in colorectal cancer cells. Expression of ESM-1 siRNA decreased cell survival through the Akt-dependent inhibition of NF-κB/IκB pathway and an interconnected reduction in phospho-Akt, -p38, -ERK1, -RSK1, -GSK-3α/ß and -HSP27, as determined by a phospho-MAPK array. ESM-1 silencing induced G(1) phase cell cycle arrest by induction of PTEN, resulting in the inhibition of cyclin D1 and inhibited cell migration and invasion of COLO205 cells. Consistently, ESM-1 overexpression in HCT-116 cells enhanced cell proliferation through the Akt-dependent activation of NF-κB pathway. In addition, ESM-1 interacted with NF-κB and activated NF-κB promoter. This study demonstrates that ESM-1 is involved in cell survival, cell cycle progression, migration, invasion and EMT during tumor invasion in colorectal cancer. Based on our results, ESM-1 may be a useful therapeutic target for colorectal cancer.

Dysregulation of overexpressed IL-32α in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-κB and Bcl-2.

IL-32 is a newly discovered cytokine. Recently, various reports suggest that it plays a role as a proinflammatory mediator and may be involved in several cancer carcinogenesis. However, IL-32 expression in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated the expression and role of IL-32α in hepatocellular carcinoma, because IL-32 was identified as an upregulated gene in hepatocellular carcinoma tissues compared to nontumorous regions using DNA microarray. IL-32α was overexpressed in tissue and serum from patients with HCC and localized in the cytoplasm and nucleus of hepatocellular carcinoma tumor cells. Moreover, secreted IL-32α concentration in the serum of patients with hepatocellular carcinoma was elevated as compared with those in the normal serum using a developed sandwich ELISA. Furthermore, IL-32α suppression in hepatocellular carcinoma decreased expression of phospho-p38 MAPK, NF-κB, and antiapoptotic protein Bcl-2 and induced expression of proapoptotic proteins as well as p53 and PUMA resulting in the suppression of cell growth and induction of intrinsic apoptosis. Based on our results, we suggest that IL-32α is involved in the progression of hepatocellular carcinoma and may be a useful biomarker for diagnosis and therapeutic target of hepatocellular carcinoma.

ESM-1 silencing decreased cell survival, migration, and invasion and modulated cell cycle progression in hepatocellular carcinoma.

Endothelial cell-specific molecule-1 (ESM-1) is a secretory proteoglycan comprising a mature polypeptide of 165 amino acids and a single dermatan sulfate. The aim of this study was to evaluate endothelial cell-specific molecule-1 (ESM-1) as a hepatocellular carcinoma (HCC) marker and to analyze the effect of ESM-1 gene silencing in hepatocellular carcinoma cells. RT-PCR and Western Blot analysis revealed overexpression of ESM-1 in human HCC liver tissue and in serum from patients with HCC. Sandwich ELISA assay was used for quantitative analysis of ESM-1 in serum. Levels of ESM-1 were significantly elevated in the serum of patients with HCC (n = 40) as compared to serum from patients with hepatitis (AH, n = 40; CH, n = 39) or liver cirrhosis (n = 40) or from healthy subjects (n = 40). The accuracy of ESM-1 for HCC was higher than that of α-fetoprotein (AFP) according to ROC curve analysis. Expression of ESM-1 siRNA decreased cell survival through the inhibition of NF-κB pathway and induced cell cycle arrest by PTEN induction resulting in the inhibition of cyclin D1 in SK-Hep1 cells. Furthermore, ESM-1 silencing inhibited cell migration and invasion of SK-Hep1 cells. This study demonstrates that ESM-1 as a potential tumor marker is overexpressed in most tissues and serum in the presence of HCC and is involved with cell survival, cell cycle progression, migration, and invasion of hepatocellular carcinoma cells. Based on our results, we suggest that ESM-1 or a combination of ESM-1 and AFP is useful markers for diagnosis of HCC and ESM-1 may be useful therapeutic target of hepatocellular carcinoma.

Development of a fluorescent microsphere immunoassay for cystatin B (CSTB) in serum of patients with hepatocellular carcinoma.

BACKGROUND: Serum cystatin B (CSTB) concentrations have been reported to be increased in patients with hepatocellular carcinoma compared to concentrations seen in normal subjects. In this study, we developed a "fluorescent microsphere immunoassay" (FMI) capable of specifically detecting CSTB in serum. METHODS: The FMI used a microparticle conjugated polyclonal antibody to CSTB and biotinylated monoclonal antibody as capture protein and probe protein, respectively. The results were obtained using the Bio-Plex(200) system. RESULTS: The dose-response relationship between CSTB and fluorescent intensity showed linearity in the range 0-1000 pg/mL and 7 pg/mL, sensitivity lower than 11.2 pg/mL. This result revealed that the FMI system was more sensitive than enzyme-linked immunoassay (ELISA). Additionally, the FMI system used smaller sample volumes compared to ELISA. CONCLUSIONS: We measured CSTB with both the FMI and an ELISA procedure and compared the two methods. The CSTB concentrations in serum specimens as measured with the FMI assay system were similar to those measured with ELISA. Thus, the new FMI using the Bio-Plex system may be useful for detection of CSTB in human serum.

Identification of endothelial cell-specific molecule-1 as a potential serum marker for colorectal cancer.

No ideal serum markers for screening colorectal cancer (CRC) have been identified. The aim of this study was to determine the usefulness of endothelial cell-specific molecule-1 (ESM-1) as a serum marker for CRC. Illumina microarray was carried out to search CRC-related biomarkers. cDNA microarray detected that ESM-1 was one of the overexpressed genes in CRC. Overexpression of ESM-1 mRNA was confirmed in tissues of CRC by RT-PCR and real-time PCR. Immunohistochemical staining showed strong expression of ESM-1 in the cytoplasm of tumor cells. Overexpression of ESM-1 in human serum with CRC was found by Western blot analysis. For quantitative analysis of ESM-1 in serum, we determined the ESM-1 levels in serum specimens using an ELISA kit. We showed that the ESM-1 levels in the serum of patients with CRC were significantly elevated (70.1 ± 29.7 pg/mL) compared to healthy subjects (29.7 ± 14.9 pg/mL). The accuracy, sensitivity, and specificity of ESM-1 for CRC were 0.94, 99%, and 73%, respectively, by receiver operating characteristics curve analysis. The positive predictive value and negative predictive value were 63% and 95%, respectively. The likelihood ratios of a positive or negative test result were 73 and 0.27, respectively. When analyzed with a Cox regression model, a higher serum ESM-1 level (≥76.0 pg/mL) was correlated with poor prognosis. This study suggests that expression of ESM-1 is increased in tissue and serum of CRC patients and that ESM-1 can be used as a potential serum marker for the early detection of CRC.

Evaluation of annexin II as a potential serum marker for hepatocellular carcinoma using a developed sandwich ELISA method.

Annexin II (Annexin A2, ANXA2) is a 36 kDa calcium-dependent phospholipid-binding protein that is located on the surface of most eukaryotic cells. ANXA2 is involved in several biological processes, including anti-inflammatory effects, Ca27+-dependent exocytosis, immune responses, Ca2+ transport and phospholipase A2 regulation. In our previous study, ANXA2 was identified as an up-regulated gene in hepatocellular carcinoma (HCC) tissue by cDNA microarray. In the present study, we have evaluated ANXA2 as a tumor-associated marker of HCC. We determined the ANXA2 levels in human liver tissues with HCC using real-time RT-PCR and Western blot analysis. For quantitative analysis of the ANXA2 protein in body fluids, we developed a sandwich ELISA system in which a polyclonal antibody and a monoclonal antibody specific to ANXA2 were employed as a capture antibody and a probe antibody, respectively. We detected the ANXA2 concentration in human serum using our newly developed system and evaluated its usefulness as a tumor marker. Overexpression of ANXA2 in human liver tissue was confirmed by real-time RT-PCR and Western blot analysis. The sandwich ELISA system for ANXA2 was developed for the detection of ANXA2 in human samples. The dose-response relationship between ANXA2 and optical density was linear in the range of 0-10 microg/ml and the sensitivity was 0.02 microg/ml. We determined the ANXA2 concentration in serum specimens using the newly developed sandwich ELISA. The serum ANXA2 concentrations of the patients with HCC (53.38+/-36.23 microg/ml) were significantly elevated when compared with those of normal individuals (28.81+/-24.94 microg/ml). These results suggest that expression of ANXA2 may be increased in HCC patients and may play an important role in liver cancer progression. This new ELISA method can be used as a tool for the detection of ANXA2 in human serum, particularly for cancer diagnostics.

Smaller neocortical gray matter and larger sulcal cerebrospinal fluid volumes in neuroleptic-naive women with schizotypal personality disorder.

CONTEXT: Structural brain abnormalities, including larger cerebrospinal fluid (CSF) volumes, have been observed in men diagnosed as having schizotypal personality disorder (SPD). OBJECTIVES: To determine whether women with SPD have abnormalities similar to those of men with SPD and to elucidate specific SPD regional volume deficits and symptom correlations. DESIGN: Naturalistic study. SETTING AND PARTICIPANTS: Thirty neuroleptic-naive women with SPD and 29 female control subjects, both recruited from the community. Participants were group matched for age, parental socioeconomic status, handedness, and IQ. INTERVENTIONS: A new segmentation method was applied to magnetic resonance images to automatically parcel the images into CSF, gray matter, and white matter. The neocortex was manually separated from subcortical and other nonneocortical structures. Voxel-based morphometry was applied to determine global and regional volume deficits. MAIN OUTCOME MEASURES: Left and right neocortical gray matter, white matter, and CSF relative volumes as well as clinical symptoms from the Structured Interview for Schizotypy and the Schizotypal Personality Questionnaire-Brief Version. RESULTS: Smaller left (3.84%) and right (3.83%) neocortical gray matter relative volumes associated with larger left (9.66%) and right (9.61%) sulcal CSF relative volumes were found in women with SPD compared with controls. Voxel-based morphometry showed that the neocortical deficits in SPD were especially prominent in the left superior and middle temporal gyri, left inferior parietal region with postcentral gyrus, and right superior frontal and inferior parietal gyri. In the SPD group, larger lateral ventricle volumes correlated with more severe symptoms on the Structured Interview for Schizotypy and the Schizotypal Personality Questionnaire-Brief Version. CONCLUSIONS: The smaller neocortical gray matter volume and larger sulcal CSF volume provide evidence of the brain basis of this personality disorder and emphasize the communality of brain abnormalities in the schizophrenia spectrum.