KCNIP4 as a candidate gene for personality disorders and adult ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children with striking persistence into adulthood and a high co-morbidity with other psychiatric disorders, including personality disorders (PD). The 4p15.31 region was shown to be associated with ADHD in several genome wide association studies (GWAS). In the present study we also report association of the 4p15.31 locus with Cluster B and Cluster C PD as identified by a pooled genome-wide association study in 400 individuals suffering from PD. The gene coding for the Kv channel-interacting protein 4 (KCNIP4) is located in this region. KCNIP4 is an interaction partner of presenilin and plays a role in a negative feedback loop in the Wnt/ß-catenin pathway. Thus, we reasoned it to be a promising candidate gene for ADHD as well as for PD. To clarify the role of KCNIP4 in those disorders, we conducted candidate gene based association studies in 594 patients suffering from adult ADHD and 630 PD patients as compared to 974 healthy control individuals. In the adult ADHD sample, six single markers and one haplotype block revealed to be associated with disease (p values from 0.0079 to 0.049). Seven markers within the KCNIP4 gene showed an association with PD (p values from 0.0043 to 0.0437). The results of these studies suggest a role of KCNIP4 in the etiology of ADHD, PD and other co-morbid disorders.

PPP2R2C as a candidate gene of a temperament and character trait-based endophenotype of ADHD.

There are several lines of evidence that the 4p16 region is a candidate locus of both attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder. None of the harbored candidate genes of this region were hitherto shown to be associated with ADHD despite promising functionality. One of the most promising candidate genes in this region is protein phosphatase 2, regulatory subunit B, gamma (PPP2R2C), which, however, thus far has not been assessed for a potential association with ADHD. A total of 513 in- and outpatients affected with adult ADHD and 536 controls as well as 170 nuclear families with 249 children affected with ADHD were genotyped for 35 SNPs, which tagged the promoter region, the 5' and 3' UTRs, and the exons of the PPP2R2C. Two independent samples provided evidence that the major G allele of rs16838844 increases risk toward ADHD. Allelic variations of PPP2R2C rs16838698 on the other hand might be associated with a variety of personality traits. There is evidence that allelic variation in PPP2R2C may be associated with a variety of personality traits and ADHD per se. Nevertheless, as all those conditions are comorbid, PPP2R2C might reflect a common underlying neurobiological risk factor.

DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders.

Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.

Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial.

BACKGROUND & AIMS: The effect of octreotide plus interferon-alpha versus octreotide monotherapy on the primary study end points of time to treatment failure (progression, death, stop of study treatment) and long-term survival was investigated in patients with progressive metastatic neuroendocrine foregut (mainly pancreatic) and midgut tumors. METHODS: One hundred nine of 125 registered patients were randomized starting in January 1995, and 105 patients (51 monotherapy, 54 combination treatment) were finally analyzed in March 2000. Tumor growth was assessed at 3-month intervals by computed tomography or magnetic resonance imaging. Long-term survival was studied up to April 2004 in all analyzed patients and in 9 patients not randomized because of stable disease. RESULTS: Partial tumor regression occurred in 2.9%, 1.9%, and 5.7% and stabilization of tumor growth in 44.8%, 27.6%, and 15.2% at 3, 6, and 12 months, respectively, with no significant differences between both treatment arms. In March 2000, 9.5% of patients were in treatment. Time to treatment failure and long-term survival did not differ significantly between the 2 groups, with a median survival of 32 and 54 months for the octreotide and the combination groups, respectively. Survival was longer in patients not randomized because of stable disease (median, 68 months) and in those with low nuclear Ki-67. A trend toward longer survival was shown for patients with slow spontaneous tumor growth before randomization. Patients responding to treatment lived longer than unresponsive patients. CONCLUSIONS: Combination treatment was not superior to monotherapy concerning progression-free and long-term survival. Patients responding to treatment and those with slow spontaneous tumor growth had a survival advantage.

Extracorporeal shock wave therapy for plantar fasciitis: randomised controlled multicentre trial.

OBJECTIVE: To determine the effectiveness of extracorporeal shock wave therapy compared with placebo in the treatment of chronic plantar fasciitis. DESIGN: Randomised, blinded, multicentre trial with parallel group design. SETTING: Nine hospitals and one outpatient clinic in Germany. PARTICIPANTS: 272 patients with chronic plantar fasciitis recalcitrant to conservative therapy for at least six months: 135 patients were allocated extracorporeal shock wave therapy and 137 were allocated placebo. MAIN OUTCOME MEASURES: Primary end point was the success rate 12 weeks after intervention based on the Roles and Maudsley score. Secondary end points encompassed subjective pain ratings and walking ability up to a year after the last intervention. RESULTS: The primary end point could be assessed in 94% (n=256) of patients. The success rate 12 weeks after intervention was 34% (n=43) in the extracorporeal shock wave therapy group and 30% (n=39) in the placebo group (95% confidence interval - 8.0% to 15.1%). No difference was found in the secondary end points. Few side effects were reported. CONCLUSIONS: Extracorporeal shock wave therapy is ineffective in the treatment of chronic plantar fasciitis.

Resource utilization and costs of stroke unit care in Germany.

OBJECTIVES: Stroke imposes a considerable economic burden on the individual and society. Recently, the concept of an integrated stroke unit has been established in several countries to improve the outcome of patients. This study evaluates the costs of acute care of the different cerebrovascular insults in a stroke unit. METHODS: The study population included 340 patients who were consecutively admitted to the Department of Neurology, Philipps University Marburg, with the diagnosis of stroke or transient ischemic attack (TIA) between January 1 and June 30, 2000. Clinical status and course were evaluated by using the Barthel index and the modified Rankin scale. Employing a "bottom-up" approach, we calculated the costs from the perspective of the hospital and the third-party payer using data from provider departments and other published sources. RESULTS: Inpatient costs were 3020 euros (3290 US dollars) for TIA, 3480 euros (3790 US dollars) for ischemic stroke (IS), and 5080 euros (5540 US dollars) for intracerebral hemorrhage (ICH) and differed significantly among these subgroups (P < .05). Patient subgroups ranked in the same order for average length of stay at 9.4 days for TIA, 10.2 days for IS, and 11.9 days for ICH (P > .05). Approximately 30% of the hospital costs are due to physician charges and care. Imaging amounted to 10% and lab investigations to 14% of total costs, independent of the diagnosis. Postacute treatment, including inpatient rehabilitation, cost 9880 euros per patient. Across all diagnostic groups, a mean clinical improvement was observed at time of discharge. CONCLUSIONS: Care of patients with cerebrovascular events in a stroke unit causes a high demand of resources and has a considerable impact on health-care expenditure. Therefore, investigations comparing the stroke unit concept with other strategies in stroke care are necessary to evaluate the stroke unit concept for a rational use of available resources in patients with cerebrovascular events.

Prospective pilot study of neoadjuvant chemotherapy with 5-fluorouracil, folinic acid and oxaliplatin in resectable liver metastases of colorectal cancer. Analysis of 42 neoadjuvant chemotherapies.

PURPOSE: Since there are currently no data available from a prospective trial, the primary objective of this prospective study was to investigate whether the rate of R0-liver resections without morbidity would be at least 50 % in patients with neoadjuvant chemotherapy for colorectal liver metastases. PATIENTS AND METHODS: 42 patients were treated with a biweekly FOLFOX regimen. Chemotherapy consisted of a 2-hour infusion of folinic acid (FOL) 500 mg/m2, followed by a 24-hour infusion of 5- fluorouracil (F) 2000 mg/m2 daily for two days. Oxaliplatin (OX) 85 mg/m 2 was given simultaneously with FOL. Treatment allocation was randomized with either 3 or 6 cycles for the final 30 patients. A liver resection was performed 2 to 5 weeks after the final infusion. RESULTS: An objective response was observed in 20 of 42 patients (response rate was 27 % higher after 6 cycles). Liver resection (R0) could be performed in 34 patients. Postoperative complications were reported in 14 patients (13 occurring within 30 days after resection) and severe complications in 5 cases (including two deaths after extended resection). Liver failure and persistent biliary fistula were the most frequently documented complications. There was no relevant difference in safety criteria between 3 and 6 applications. CONCLUSION: The use of neoadjuvant chemotherapy in resectable liver metastases induced significant remissions without increasing morbidity. The rate of severe complications and cases of no R0-resection in this study was 31 % and was with that significantly lower than 50 % (95 % CI 17.6 %-47.1 %). The risk to the patient is therefore acceptable when undergoing neoadjuvant treatment in a prospective intergroup trial.