Reduced expression of THRß in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression.

PURPOSE: Down-regulation of thyroid hormone receptor beta (THRß) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRß mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical-biological features. METHODS: Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRß gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRß. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. RESULTS: THRß transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRß expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. CONCLUSIONS: Our results demonstrate that down-regulation of THRß is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis.

Regulation of sodium/iodide symporter and lactoperoxidase expression in four human breast cancer cell lines.

BACKGROUND: Agents capable of increasing radioiodine concentration by stimulating the sodium/iodide symporter (NIS) expression have been extensively investigated for the treatment of certain well-differentiated breast cancers. AIM: In this study, we analyzed the regulation of the NIS and lactoperoxidase (LPO) gene expression in 4 different human breast cancer cell lines, representative of different histotypes of breast cancer. METHODS: MCF-7, T-47D, MDA-MB231, and HCC-1937 (the latter carrying the BRCA-1 mutation) were exposed to different stimulators and the levels of NIS and LPO mRNA measured by a quantitative RT-PCR. RESULTS: All-trans-Retinoic Acid (RA), Dexamethasone (DEX), Trichostatin A (TSA), and Sodium Butyrate (NaB) induced the expression of NIS mRNA in MCF-7 and T-47D cell lines, whereas HCC-1937 and MBA-MB231 were slightly responsive only to the histone-deacetylase inhibitors TSA and NaB. Minor stimulatory effects were detected on LPO mRNA in MCF-7 and T-47D treated with TSA and NaB or RA only in MCF-7, while no effect was detectable in the other two cell lines. CONCLUSIONS: These data indicate that retinoic acid, alone or in combination with DEX, as well as HDAC-inhibitors are very promising agents for a radioiodine- based therapy in a large spectrum of breast cancers, including neoplasms from both basal and ductal cells, especially for the well-differentiated estrogen-dependent tumors. Other molecules or other drug combinations should be tested to extend the same strategy to the less differentiated and more aggressive tumor cells, including those carrying the BRCA mutation.

Agglutinating specificity for LW factor in guinea pig and rabbit anti-Rh serums.

Serums produced in guinea pigs or rabbits inocutlated with monkey (rhesuts or baboon) or human red cells contain the same high-incidence agglutinating activity found in human antiLW serumls. After one absorption with LW-negative blood cells. anti-LW specificity, was observed with stronger reactions on Rh-positive than Rh-megative cells. The 85-percent specificity was obtained after complete absorption with Rh-negative blood.

Cytotoxic effects of a novel pyrazolopyrimidine derivative entrapped in liposomes in anaplastic thyroid cancer cells in vitro and in xenograft tumors in vivo.

In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 microM Si 34 determined a decrease of cell counts by approximately 25% and approximately 75% compared with those of control cells respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 microM increased cell mortality also ( approximately 29% and approximately 18% respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 microM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of epidermal growth factor-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, the growth of tumor xenografts induced in severe combined immunodeficiency (SCID) mice was inhibited by i.v. administration of 25-50 mg/kg of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.

[Hepatitis type A with atypical course]. / Epatite A ad evoluzione atipica.

Hepatitis A virus infection is usually asymptomatic in children. Classic symptomatic forms and atypical clinical manifestations are known. We report a paediatric case of hepatitis A with marked cholestasis, treated with steroids, and with an unusual prolonged course.

[Acute acalculous cholecystitis as a complication of hepatitis A: report of 2 pediatric cases]. / Colecistite acuta acalcolotica in corso di epatite A: 2 casi pediatrici.

Acute acalculous cholecystitis (CAA) is very rare in children and it is usually related to infectious agents. We report 2 paediatric cases of CAA complicating hepatitis type A, with a favourable evolution with conservative treatment.

Growth inhibition of medullary thyroid carcinoma cells by pyrazolo-pyrimidine derivates.

There is no effective treatment for recurrent or metastatic medullary thyroid carcinoma (MTC), a tumor arising from thyroid C-cells commonly presenting an inherited or acquired RET mutation. In this study we examined the sensitivity of two human MTC cell lines to novel pyrazolopyrimidine derivates, able to inhibit src-family tyrosine kinase activity. In TT cells [carrying the multiple endocrine neoplasia (MEN)2A Ret mutation Cys 634Trp] and MZ-CRC-1 cells (carrying the MEN2B RET mutation Met891Thr), one of these compounds, namely Si 34, determined a significant growth inhibitory effect (approximately 90% vs control for TT, 80% vs control for MZ-CRC-1) mainly due to enhanced cell mortality after a 6-day incubation. At concentrations that increased cell mortality, neither biochemical or morphological characteristics of apoptosis were detected in TT and MZCRC- 1 cells treated with Si 34. These results, when confirmed in other in vivo preclinical models, suggest that this novel tyrosine kinase inhibitor may be useful for the treatment of MTC.

Early Prediction of Cardiovascular Disease in Kidney Transplant Recipients.

Cardiovascular disease (CVD) is frequent after kidney transplantation (KT). This study investigated CVD prediction in KT by information available before KT or within 6 months after KT. The study cohort consisted of 629 patients with KT in 2005-10 and with adult age at KT. The end point was incidence up to 2015 of CVD (coronary heart disease, cerebrovascular disease, peripheral artery disease). Graft failure, non-CVD death with functioning graft, and loss to follow-up were considered competing events. CVD prediction was investigated for 34 variables by means of competing-risks regression. Follow-up range was 0.28-10.00 years (mean ± SD, 7.30 ± 3.10). First incident event was CVD in 103 patients and competing events in 146 patients. In the multivariable model for pre-KT variables only, CVD predictors were male sex (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.06-2.66), diabetic nephropathy (HR, 6.63; 95% CI, 1.81-24.35), pre-KT dialysis for ≥5 years (HR, 1.52; 95% CI, 1.02-2.27), pre-KT CVD (HR, 4.87; 95% CI, 2.84-8.35), and age at KT ≥45 years (HR, 2.98; 95% CI, 1.83-4.87). In the model for pre-KT and post-KT variables together, the sole post-KT CVD predictor was estimated glomerular filtration rate <60 mL/min at the 6-month visit (HR, 1.75; 95% CI, 1.11-2.77). Diabetic nephropathy, pre-KT dialysis, pre-KT CVD, and age at KT predicted 91.2% of incident CVD. Early available information effectively predicted CVD in KT independently from competing events.

Migraine with aura and white matter abnormalities: Notch3 mutation.

The authors report on an Italian family with eight affected members who show autosomal dominant migraine with prolonged visual, sensory, motor, and aphasic aura. These symptoms are associated with white matter abnormalities on brain MRI. All living affected members carry a Notch3 mutation (Arg153Cys) previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). White matter abnormalities occur in a variable percentage of the general migraine population; CADASIL should be suspected in migraineurs with prolonged atypical aura and white matter abnormalities.

Expression of adenylyl cyclase types III and VI in human hyperfunctioning thyroid nodules.

Hyperfunctioning thyroid nodules are characterized by the presence of spontaneous somatic mutations responsible for constitutive activation of the cAMP pathway. However, alterations affecting other elements of the cAMP signaling system may counteract the effects of the mutations. In this study, the expression of the adenylyl cyclase (AC) types III and VI was investigated by Western blot in 18 hyperfunctioning thyroid nodules; in 12 samples, we also assessed the presence of TSH receptor (TSHR) or gsp mutations and levels of AC VI and III mRNA. We found that the expression of nodular AC VI (but not AC III) was significantly lower (85.1% of normal, P=0.014) than the expression of both adenylyl cycles types of perinodular tissue from the same patients. Slightly, but not significant differences were detected in nodules with or without mutations and AC protein levels generally showed correlation with the levels of the transcripts detected by RT-PCR. In addition, AC III and AC VI expression levels within a given nodule were characterized by a significant positive correlation. These findings indicate that a diminished expression of AC type VI may be part of the mechanisms occurring in the hyperfunctioning nodules, independently of the presence of TSHR or gsp mutations, which influence the resulting phenotype.

APE/Ref-1 is increased in nuclear fractions of human thyroid hyperfunctioning nodules.

Apurinic/apyrimidinic endonuclease APE/Ref-1 is a multifunctional protein provided with DNA repair, transcription-factor regulation and anti-apoptotic activities. We have previously reported that, in thyroid cells, TSH regulates both the synthesis and nuclear translocation of APE/Ref-1. We have also shown that nuclear levels of this protein are reduced both in thyroid carcinoma tissues and cell lines. In the present study, APE/Ref-1 expression and cellular localization were analysed by Western blot in hyperfunctioning thyroid nodules from patients with toxic adenoma and/or toxic multinodular goiter. The total content of APE/Ref-1 protein was increased in the majority of the hyperfunctioning tissues with respect to normal adjacent tissue. There was also an increase in the nuclear levels of APE/Ref-1, suggesting enhanced cytoplasm-to-nucleus translocation of the protein in addition to its increased rate of synthesis. These results demonstrate that the phenomenon of nuclear translocation of APE/Ref-1 hypothesized on the basis of cell culture experiments does actually occur in vivo. Together with previous observations in thyroid carcinomas and tumoral cell lines, our findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: an early stage characterized by simple hyperplasia and upregulation of APE/Ref-1 in the nuclear compartment of the cell and a later stage in which nuclear levels of the protein drop to below-normal levels as the cell becomes progressively undifferentiated.

A cultural perspective on family theory and therapy.

Although family therapists' conceptualizations of culture include ethnicity, nationality, religion, generation, gender, class, and sexual orientation, this article focused on ethnicity and families in the United States. A review of the literature reveals that effective family therapy is both sensitive to the family's cultural heritage and attuned to the unique interactional patterns, attitudes, feelings, and behaviors of each family with whom the therapist works. Culturally sensitive family therapy attempts to transcend cultural barriers, while respecting the cultural identity and integrity of the individual family members, the family unit as a whole, and the therapist. As multiculturalism has become increasingly emphasized in the United States, family therapists are challenged to facilitate families' efforts to reconnect with their cultural heritage to preserve a sense of belonging and identity, while simultaneously helping them adapt to their evolving cultural context.

The development of decoding of emotions in children with externalizing behavioral disturbances and their normally developing peers.

This investigation examined children's capacity to decode verbal and nonverbal emotional stimuli. Children with externalizing behavioral symptoms were compared to two types of controls, including chronically ill and normally developing children. Children were requested to identify whether video scenes were happy, angry, sad, or neutral, across four different modalities including verbal, prosody, facial, and combined. Findings were that chronological age was a significant predictor of children's ability to decode emotions with older children having better developed abilities than their younger peers. Verbal intelligence also was found to be a significant predictor of the ability to decode facial expressions and combined scenes. Although the data did not support the original hypotheses that children with externalizing behavior disorders would be less accurate than controls in the decoding of emotions, findings did support a developmental progression of decoding accuracy. Recommendations within the limitations of the study design are provided which support a developmental framework in children's acquisition of the decoding of emotions.

Treatment of traumagenic beliefs among sexually abused girls and their mothers: an evaluation study.

The objective of this study was to evaluate and compare the efficacy of two short-term individual therapy interventions for sexually abused girls and their nonoffending female caretakers. Thirty-two girls, ages 8 to 13, and their caretakers from primarily low-income, African-American families were randomly assigned to a theoretically based, structured experimental treatment program or to a relatively unstructured comparison intervention. Measures of child outcome were completed before and after the treatment program by each parent and child, and by a clinician blind to treatment condition. Pre- and postmeasures of maternal outcome were completed by the caretaker and a clinician not involved in the treatment. Both treatment programs yielded decreases in children's posttraumatic stress disorder symptoms and traumagenic beliefs reflecting self-blame and powerlessness, and increases in children's overall psychosocial functioning. The experimental intervention was more effective than the comparison program in increasing abuse-related caretaker support of the child and in decreasing caretaker self-blame and expectations of undue negative impact of the abuse on the child. Clinical implications of these findings include the development of interventions targeting sexually abused children's traumagenic beliefs and nonoffending parents' support of their victimized children.

The Amblyopia Treatment Index.

OBJECTIVE: To develop a questionnaire to assess the acceptability of amblyopia treatment and its effect on the child and family. METHODS: A 20-item parental survey was developed and pilot tested on 64 subjects, aged 3 to 6 years, participating in the Amblyopia Treatment Study, a randomized trial comparing patching and atropine as treatments for moderate amblyopia. The survey was administered after 4 weeks of treatment. A descriptive item analysis and an internal consistency reliability analysis were performed. RESULTS: Nineteen of the 20 items demonstrated adequate variability as evidenced by the frequency distributions for item responses. Only 4 (<1%) of 1280 possible item responses were missing, one each by 4 different respondents. Factor analysis identified 3 treatment-related factors--"adverse effects," "compliance," and "social stigma"--among 11 of the 20 items. The internal-consistency reliability alpha for the 5-item adverse effects subscale was 0.82, the 4-item compliance subscale alpha was 0.81, and the 2-item social stigma subscale alpha was 0.84. CONCLUSIONS: The Amblyopia Treatment Index appears to be a useful instrument for assessing the impact of amblyopia treatment in 3- to 6-year-old children.

Predicting symptomatology and self-blame among child sex abuse victims.

Fifty-six sexually-abused girls and their nonoffending female caretakers from primarily low-income. African American families were comprehensively assessed in order to determine factors related to child symptomatology and self-blame. Girls whose overall relationships with their caretakers were somewhat negative exhibited more behavioral difficulties. Girls with disruptions in their relationship with a primary caretaker and who felt powerless as a result of the abuse were rated as functioning less well overall by clinicians. Child age, general attributional style, and caretaker blame of the child were related to child self-blame. Clinical implications of these findings include identification of clients at high risk for negative sequelae and development of interventions targeted at specific clinical issues.

Meningeal carcinomatosis in patient with esophagus adenocarcinoma.

Meningeal carcinomatosis (MC) is an uncommon from of metastasis of solid tumors. We reported a clinical case of a woman with esophagus adenocarcinoma that a few months after surgical operation, presented episodes of vomiting, nausea, hypertension, mental change, unconsiousness; A contrast-enhanced CT of the brain revealed an "area of enhancement in the caudate nucleus" and cerebrospinal fluid cytologic studies evidenced the presence of carcinomatous cells. The clinical state of the patient deteriorated and she died a few days later. Autopsy confirmed meningeal carcinomatosis without parenchymal involvement.

Revenge of the mutant cockroach: culturally adapted storytelling in the treatment of a low-income African American boy.

A clinical case is presented in which a culturally adapted storytelling technique was used in child therapy with a socioeconomically disadvantaged African American boy. In this intervention, the child and therapist co-created a story by taking turns adding to the story during therapy sessions. The child's contributions to the story were interpreted by taking into account his sociocultural context, and the therapist's responses were adapted to reflect relevant sociocultural factors. Advantages of storytelling techniques in child therapy are presented, and issues to consider when using these techniques with culturally diverse populations are discussed.

Learning, school performance, and children with asthma: how much at risk?

Children with asthma may be at risk for decreased school functioning due to acute exacerbations, increased absenteeism, iatrogenic effects of their asthma medication, and the stress associated with a chronic illness. The purpose of this article is to critically review extant research pertaining to the school functioning of children with asthma, including studies of school attendance, school performance, the effects of asthma medications on learning and behavior, and the role of psychological variables in the development of functional impairments. There is not sufficient evidence to suggest that children with asthma are at significantly higher risk for poor school performance than children without asthma. Factors that may contribute to poor school performance among children with asthma include iatrogenic effects of oral steroids, poor medical management of the disease, and psychological problems. Recommendations for improving the school functioning of children with asthma are discussed.

Activities and games for group psychotherapy with sexually abused children.

As increasing attention is given to the practice of group psychotherapy with sexually abused children, clinicians are using games and activities designed to address issues related to sexual abuse and its prevention. This paper describes how specific games and activities can be used in group therapy with child victims. These games and activities include: prevention films, role plays, and communication board games. Benefits and risks associated with the use of these resources are also discussed.