Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly

Pituitary adenomas account for 10-15% of primary intracranial tumors. Growth hormone (GH)-secreting adenomas account for 13% of all pituitary adenomas and cause acromegaly. These tumors can be aggressive, invade surrounding structures and are highly recurrent. The objective of this study was to evaluate E-cadherin, Slug and neural cell adhesion molecule (NCAM) expression in GH-secreting pituitary adenomas and its relationship to tumor invasiveness. A cross-sectional study of patients who underwent hypophysectomy due to GH-secreting pituitary adenoma from April 2007 to December 2014 was carried out. The medical records were reviewed to collect clinical data. Immediately after surgery, tumor samples were frozen in liquid nitrogen and stored in a biofreezer at -80°C for assessment of E-cadherin 1 (CDH1), SLUG (SNAI2), and NCAM (NCAM1) by real-time PCR. The samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis of E-cadherin and NCAM. Thirty-five patients with acromegaly were included in the study. Of these, 65.7% had invasive tumors. Immunohistochemically, E-cadherin was expressed in 96.7% of patients, and NCAM in 80% of patients. There was no statistically significant relationship between tumor grade or invasiveness and immunohistochemical expression of these markers. Regarding gene expression, 50% of cases expressed CDH1, none expressed SNAI2, and 53.3% expressed NCAM1. There was no statistically significant relationship between tumor grade or invasiveness and gene expression of CDH1, SNAI2, and NCAM1. The absence of Slug overexpression and of E-cadherin and NCAM suppression suggests that expression of these markers is not associated with tumor invasiveness in GH-secreting pituitary adenomas.

Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly.

Pituitary adenomas account for 10-15% of primary intracranial tumors. Growth hormone (GH)-secreting adenomas account for 13% of all pituitary adenomas and cause acromegaly. These tumors can be aggressive, invade surrounding structures and are highly recurrent. The objective of this study was to evaluate E-cadherin, Slug and neural cell adhesion molecule (NCAM) expression in GH-secreting pituitary adenomas and its relationship to tumor invasiveness. A cross-sectional study of patients who underwent hypophysectomy due to GH-secreting pituitary adenoma from April 2007 to December 2014 was carried out. The medical records were reviewed to collect clinical data. Immediately after surgery, tumor samples were frozen in liquid nitrogen and stored in a biofreezer at -80°C for assessment of E-cadherin 1 (CDH1), SLUG (SNAI2), and NCAM (NCAM1) by real-time PCR. The samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis of E-cadherin and NCAM. Thirty-five patients with acromegaly were included in the study. Of these, 65.7% had invasive tumors. Immunohistochemically, E-cadherin was expressed in 96.7% of patients, and NCAM in 80% of patients. There was no statistically significant relationship between tumor grade or invasiveness and immunohistochemical expression of these markers. Regarding gene expression, 50% of cases expressed CDH1, none expressed SNAI2, and 53.3% expressed NCAM1. There was no statistically significant relationship between tumor grade or invasiveness and gene expression of CDH1, SNAI2, and NCAM1. The absence of Slug overexpression and of E-cadherin and NCAM suppression suggests that expression of these markers is not associated with tumor invasiveness in GH-secreting pituitary adenomas.

Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence.

Meningiomas are common, usually benign tumors of the central nervous system that have a high rate of post-surgical recurrence or regrowth. We determined expression of the proteins merlin, NDRG2, ERBB2, and c-MYC in meningiomas using immunohistochemistry and assessed relationships between protein expression and gender, age, tumor grade, and recurrence or regrowth. The study sample comprised 60 patients, (44 women and 16 men) with a mean age of 53.2 ± 12.7 years. Tumors were classified as grade I (n=48) or grades II and III (n=12). Expression of merlin, NDRG2, ERBB2, and c-MYC was not significantly different statistically with relation to gender, age, or meningioma recurrence or regrowth. Merlin was expressed in 100% of the cases. No statistically significant difference between tumor grade and recurrence or regrowth was identified. Statistically significant differences were identified between the mean age of patients with grade I (54.83 ± 11.60) and grades II and III (46.58 ± 15.08) meningiomas (P=0.043), between strong c-MYC expression and grades II and III (P<0.001), and between partial surgical resection and tumor recurrence or regrowth (P<0.001). These findings reveal the lower mean age among grades II and III meningioma patients than grade I patients, the influence of the protein merlin on tumorigenesis, the association of c-MYC with aggressive meningiomas, and that partial surgical resection is associated with tumor recurrence or regrowth.

Catalysts for CO2/epoxide ring-opening copolymerization.

This article summarizes and reviews recent progress in the development of catalysts for the ring-opening copolymerization of carbon dioxide and epoxides. The copolymerization is an interesting method to add value to carbon dioxide, including from waste sources, and to reduce pollution associated with commodity polymer manufacture. The selection of the catalyst is of critical importance to control the composition, properties and applications of the resultant polymers. This review highlights and exemplifies some key recent findings and hypotheses, in particular using examples drawn from our own research.

Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence

Meningiomas are common, usually benign tumors of the central nervous system that have a high rate of post-surgical recurrence or regrowth. We determined expression of the proteins merlin, NDRG2, ERBB2, and c-MYC in meningiomas using immunohistochemistry and assessed relationships between protein expression and gender, age, tumor grade, and recurrence or regrowth. The study sample comprised 60 patients, (44 women and 16 men) with a mean age of 53.2±12.7 years. Tumors were classified as grade I (n=48) or grades II and III (n=12). Expression of merlin, NDRG2, ERBB2, and c-MYC was not significantly different statistically with relation to gender, age, or meningioma recurrence or regrowth. Merlin was expressed in 100% of the cases. No statistically significant difference between tumor grade and recurrence or regrowth was identified. Statistically significant differences were identified between the mean age of patients with grade I (54.83±11.60) and grades II and III (46.58±15.08) meningiomas (P=0.043), between strong c-MYC expression and grades II and III (P<0.001), and between partial surgical resection and tumor recurrence or regrowth (P<0.001). These findings reveal the lower mean age among grades II and III meningioma patients than grade I patients, the influence of the protein merlin on tumorigenesis, the association of c-MYC with aggressive meningiomas, and that partial surgical resection is associated with tumor recurrence or regrowth.

Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence

Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6±14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.

Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence.

Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6 ± 14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.

[The health economics of attention deficit hyperactivity disorder in Germany. Part 1: Health care utilization and cost of illness]. / Gesundheitsökonomie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung in Deutschland Teil 1: Versorgungsepidemiologie und Krankheitskosten.

In the German region of Nordbaden, 5% of children (aged 7-12 years) and 1.3% of adolescents (aged 13-19 years) were diagnosed with attention deficit hyperactivity disorder (ADHD) in 2003. About two thirds of these patients were not seen by a physician specialized in psychiatry. Now the National Association of Statutory Health Insurance Physicians in Germany (Kassenaerztliche Bundesvereinigung, KBV) has developed a proposal for the integrated provision of care for these patients, combining a guidelines-oriented multidisciplinary approach with a system of quality assurance. Against this background, currently available ADHD-related data are presented, covering epidemiology, comorbidity and differential diagnosis, health care utilization, and cost of illness. According to administrative data analyses from Nordbaden, direct medical costs for patients with ADHD, from the perspective of statutory health insurance (SHI), exceed those of matched controls by a factor of >2.5. On this basis, ADHD-related expenditures of the German SHI may be estimated at around EUR 260 million in 2003, and almost certainly will have continued to grow further since. In addition to this, a diagnosis of ADHD is associated with substantial indirect cost. Although the literature on the burden of ADHD is incomplete, it seems plausible that the cost of illness might be comparable to that reported for alcohol and addiction disorders. Thus we anticipate an increasing relevance of formal health economic evaluations of health care programs offered to patients with ADHD.

[The health economics of attention deficit hyperactivity disorder in Germany. Part 2: Therapeutic options and their cost-effectiveness]. / Gesundheitsökonomie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung in Deutschland. Teil 2: Therapeutische Optionen und ihre Kosteneffektivität.

Attention deficit hyperactivity disorder (ADHD) has been associated with a continuous increase of health care utilization and thus expenditures. This raises the issue of cost-effectiveness of health care provided for patients with ADHD. Comparative health economic evaluations generate relevant insights and typically report incremental cost-effectiveness ratios (ICERs) of alternatives versus an established standard. Typically, results of cost-effectiveness analyses (CEAs) are reported in terms of incremental cost-effectiveness ratios (ICERs). International evaluations, as well specific adaptations to Germany, indicate an acceptable to attractive cost-effectiveness--according to currently used international benchmarks--of an intense medication management strategy based on stimulants, primarily methylphenidate, with ICERs ranging from 20,000 EUR to 37,000 EUR per quality-adjusted life year (QALY) gained. Economic modeling studies also suggest cost-effectiveness of long-acting modified-release preparations of methylphenidate, owing to improved treatment compliance associated with simplified once daily administration schemes. Atomoxetine, in contrast, appears economically inferior compared to long-acting stimulants, given its higher acquisition costs and at best equal clinical effectiveness. There are currently no data supporting the cost-effectiveness of psychotherapeutic or behavioral interventions. Economic evaluations, which have been published to date, are generally limited by time horizons of up to 1 year and by their prevailing focus on ADHD core symptom improvement only. Therefore, further research into the cost-effectiveness of ADHD treatment strategies seems warranted.

Symptom control in children and adolescents with attention-deficit/hyperactivity disorder on switching from immediate-release MPH to OROS MPH Results of a 3-week open-label study.

AIM: The aim of this study was to assess the impact of switching from immediate-release (IR) methylphenidate (MPH) to OROS MPH (CONCERTA, a once-daily long-acting MPH formulation, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: Subjects with ADHD aged 6-16 (n=105),who were stably maintained on their current IR MPH regimen (10-60 mg/day), were switched to 18, 36 or 54 mg OROS MPH once daily for 21 days, depending on pre-study daily MPH dose. ADHD symptoms were assessed by parents, teachers and investigators. RESULTS: By Day 21, parent/caregiver IOWA Conners ratings had decreased from baseline by 2.7 points to 5.2 (I/O), and by 1.8 points to 5.0 (O/D). Teacher IOWA Conners ratings were maintained. Decreases in IOWA Conners ratings are indicative of ADHD symptom improvement. Approximately 75% of parents and investigators rated therapy as good or excellent. OROS MPH therapy was well tolerated. CONCLUSIONS: Switching from IR MPH to OROS MPH maintained and may have improved symptom control in children and adolescents with ADHD, during the course of this study. The changes in parent/caregiver IOWA Conners ratings suggest that OROS MPH improves symptom control in the after-school period. This is consistent with the 12-h duration of action previously demonstrated for OROS MPH.

12-month efficacy and safety of OROS MPH in children and adolescents with attention-deficit/hyperactivity disorder switched from MPH.

PURPOSE: The aim of this study was to evaluate long-term clinical treatment with OROS methylphenidate (MPH) (Concerta) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had been previously treated with immediate release (IR) MPH. METHODS: Subjects aged 6-16 years (n=105) who were stable on IR MPH (10-60 mg/day) were switched to 18, 36 or 54 mg OROS MPH once daily for 21 days, depending on prestudy MPH dose. Subjects who benefited from OROS MPH could continue in a 12-month extension period. ADHD symptoms and treatment response were assessed by parents/caregivers and investigators. RESULTS: Out of 105 enrolled children, 101 completed the 21-day treatment phase. In all, 89 parents/caregivers (88.1%) wanted their child to continue with the study treatment into the extension phase, and 56 children (63 %) completed the 1-year trial. The parent/caregiver global assessment of satisfaction ranged from 49 to 69% during the extension phase, and 49 to 71% of investigators rated the treatment as adequate. Efficacy and satisfaction were found more commonly in patients in the older age group (10-16 years), those on a higher dose (36 mg or 54 mg) and with the predominantly inattentive ADHD subtype. OROS MPH was well tolerated. CONCLUSIONS: Children and adolescents can effectively and safely be switched from IR MPH to OROS MPH with improved symptom control and compliance.

[Tools for the diagnosis of attention-deficit/hyperactivity disorder in adults. Self-rating behaviour questionnaire and diagnostic checklist]. / Instrumente zur Diagnostik der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im ErwachsenenalterSelbstbeurteilungsskala (ADHS-SB) und Diagnosecheckliste (ADHS-DC).

We report on the development of a German self-rating behaviour questionnaire (ADHD-SR) and diagnostic checklist (ADHD-DC) for the diagnosis of attention-deficit/hyperactivity disorder in adults according to DSM IV and ICD 10 research criteria. When comparing self-rating with expert rating, we found good concordance measured by intraclass coefficients on the level of single symptoms and syndrome scores. High retest reliability of the ADHD-SR demonstrated the ability to assess time-stable behaviour traits. Evaluation of the psychometric properties revealed good internal consistency and adequate convergent and divergent validity measured by the "big five" derived from the NEO-FFI and the constructs impulsivity, venturesomeness, and empathy of Eysenck's impulsiveness questionnaire. We detected a remarkable correlation with the Wender Utah Rating Scale, which targets the detection of childhood ADHD symptoms. Diagnostic sensitivity for different cutoff points was calculated by ROC analysis at 65--88%. Specificity was 67% to 92%.

[Wender Utah rating scale. The short-version for the assessment of the attention-deficit hyperactivity disorder in adults]. / Wender Utah Rating Scale (WURS-k) Die deutsche Kurzform zur retrospektiven Erfassung des hyperkinetischen Syndroms bei Erwachsenen.

This work presents a statistical analysis of the German version of the Wender Utah rating scale (WURS) for the retrospective diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adults. Data were obtained from 703 subjects. Item selection according to item-total correlation scores, frequency, and plausibility led to a short version of the scale that includes 21 items with item-total correlations from 0.19 to 0.61. Retest reliability of the WURS-k was r=0.9.

[Attention and hyperactivity disorder in children. Early detection--preventing social consequences]. / Aufmerksamkeits- und Aktivitätsstörung bei Kindern. Früh erkennen--soziales Abrutschen verhindern.

Attention deficit and activity disorder is characterized by impaired concentration, increased impulsiveness and motor restlessness. In a high percentage of cases, the symptoms persist into adulthood. Untreated victims have an increased risk of: failing to realize their full potential with regard to school-leaving performance, of developing substance dependence, of dissocial development, and of becoming more prone to accidents during leisure activity, in traffic and at work. The treatment strategies recommended in guidelines issued by the German societies of child and adolescent psychiatry are evidence-based and reliably effective.

Children with comorbid attention-deficit-hyperactivity disorder and tic disorder: evidence for additive inhibitory deficits within the motor system.

For children with attention-deficit-hyperactivity disorder (ADHD) or tic disorder (TD), we recently reported deficient inhibitory mechanisms within the motor system by using transcranial magnetic stimulation. These deficits--stated as reduced intracortical inhibition in ADHD and shortened cortical silent period in TD--could be seen as neurophysiological correlates of motor hyperactivity and tics, respectively. To investigate neurophysiological aspects of comorbidity, we measured motor system excitability for the first time also in children with combined ADHD and TD. The findings of a reduced intracortical inhibition as well as a shortened cortical silent period in these comorbid children provide evidence for additive effects at the level of motor system excitability.

A study of cranial computer tomograms in very early and early onset schizophrenia.

The cranial computer-assisted tomograms of 19 patients suffering from schizophrenic psychoses with onset by age of 14 were examined. The emphasis was on the extent of the inner liquor spaces. Compared to healthy controls, at the beginning of illness a significant enlargement was revealed only in the patient group with very early onset schizophrenia (VEOS, onset prior to the age of 12), whereas children with early onset (EOS, 12 to 14 years of age) showed no significant brain pathology. As a second result, an increase in the extent of the inner liquor spaces seems to correlate with the duration of illness. It is therefore concluded that psychoses interfere with neurodevelopmental processes and cause more severe brain pathology in very young children, already detectable at the onset of the illness. EOS, on the other hand, induces progressive morphological abnormalities over the course of the illness.

Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate.

In children with attention-deficit hyperactivity disorder (ADHD), motoric hyperactivity is one of the striking abnormalities. Because this symptom might be due to an insufficient motor control, motor system excitability in 18 drug-naive ADHD-children aged 8-12 years was compared to 18 age-matched healthy children using the technique of transcranial magnetic stimulation (TMS). Whereas motor thresholds, cortical silent period, and intracortical facilitation did not differ between the two groups, ADHD-children had significantly reduced intracortical inhibition compared to healthy controls. In all ADHD-children, a second TMS could be started after their first intake of 10 mg methylphenidate. Under this medication, a significant enhancement in intracortical inhibition could be stated. This study provides the first evidence for inhibitory deficits within the motor cortex in ADHD-children and for an enhancement of inhibitory mechanisms in this brain region by methylphenidate.