Progressive loss of cerebellar volume in childhood-onset schizophrenia

OBJECTIVE: Childhood-onset schizophrenia is a severe and unremitting form of the disorder. Prospective brain magnetic resonance imaging (MRI) studies have found progressive loss of total cerebral volume during adolescence, primarily attributable to accelerated loss of cortical gray matter. Because there is evidence of cerebellar involvement in schizophrenia, the authors examined cerebellar volume and its relation to cortical gray matter development during adolescence in patients with childhood-onset schizophrenia and healthy comparison subjects. METHOD: Total cerebellar volume was algorithmically calculated for 108 anatomical brain MRI scans from 50 patients (20 of whom were female) and 101 scans from 50 age- and gender-matched healthy volunteers (20 of whom were female). The age range of the patients and comparison subjects was 8 to 24. Midsagittal vermal area and posterior-inferior vermal lobe volume were measured by hand. Prospective rescans were obtained at approximately 2-year intervals. Cross-sectional and longitudinal data were combined in mixed model regressions to compare developmental changes for the groups. RESULTS: In contrast to healthy volunteers, patients with schizophrenia showed a progressive loss of cerebellar volume during adolescence. Cerebellar and cerebral volume decreases were significantly correlated in childhood-onset schizophrenia. CONCLUSIONS: Childhood-onset schizophrenia is associated with significant progressive loss of cerebellar volume during adolescence, consistent with previously reported decreases in total cerebral and cortical gray matter. At least in these patients with severe early-onset schizophrenia, the loss appears secondary to a generalized process.     

A 20-year longitudinal observational study of somatic antidepressant treatment effectiveness

OBJECTIVE: This observational study examined the effectiveness of somatic antidepressant treatments as administered in the community. METHOD: The study group consisted of 285 subjects with an intake diagnosis of major depressive disorder who had entered the National Institute of Mental Health Collaborative Depression Study as early as 1978, had at least one additional affective episode, and had been followed for up to 20 years, as recently as 1999. The characteristics that distinguished subjects receiving various levels of somatic antidepressant treatment were accounted for in what was called a propensity for treatment intensity model. The effectiveness of somatic antidepressant treatment during major affective episodes was then examined. RESULTS: Those who received higher levels of antidepressant treatment tended to have more prior episodes, more severe depressive symptoms, and more intensive somatic therapy during prior episodes and prior well intervals than those who received lower levels. Treatment effectiveness analyses that were stratified by propensity for treatment intensity demonstrated that those who received higher levels of antidepressant treatment were significantly more likely to recover from affective episodes. In contrast, those treated with lower levels were no more likely to recover than those who did not receive somatic treatment. CONCLUSIONS: Despite the indications of more severe depressive illness, those who received higher levels of somatic antidepressant treatment were more likely to recover from recurrent affective episodes. Results from this observational study extend the generalizability of reports from randomized clinical trials of antidepressants to a wider, more representative group of individuals who suffer from major depression.     

Directed evolution towards protease-resistant hirudin variants

Hirudin, a thrombin-specific inhibitor, is efficiently digested and inactivated by proteases with pepsin- and chymotrypsin-like specificity. Using a combination of phage display selection and high-throughput screening methods, several variants of recombinant hirudin were generated. Only very few variants comprising amino acid substitutions in the amino-terminal domain (residues 1-5) and in the carboxyl-terminal tail (residues 49, 50, and/or 56, 57, 62-64) were identified that showed thrombin inhibition activities similar to those of the wild-type polypeptide. Analysis of protease susceptibility, however, revealed that mutations, which conferred protease resistance, simultaneously diminish thrombin inhibition activity. This is particularly apparent for substitutions in the region of residues 56-64, which forms a large number of electrostatic and hydrophobic interactions with thrombin in the crystal structure of the complex. Unlike wild-type hirudin, the variant comprising Pro(50)- ...-His(56)-Asp(57)- ...-Pro(62)-Pro(63)-His(64) is completely resistant to pepsin and chymotrypsin cleavage; however, this is at the expense of thrombin inhibition activity where there is a 100-fold increase in the IC50 value. The frequent replacement of wild-type amino acids by proline at major protease cleavage sites indicates that at least pepsin- and chymotrypsin-like enzymes may exhibit a (conformational) specificity concerning the P1 and P2 positions. On the basis of these results, proline substitutions appear to be a general strategy to design polypeptides that are not susceptible to digestion by a broader range of different proteases.     

Klinische Symptomatik: "Zöliakie, ein Eisberg"

Zusammenfassung Die neuen kombinierten serologischen Testverfahren mit hoher diagnostischer Signifikanz lassen als Screeningverfahren das Ausmaß bisher unerkannter Zöliakiefälle erahnen. In Deutschland ist von einer Prävalenz von 1:500 auszugehen. Die klinische Symptomatik der Zöliakie ist in Abhängigkeit von Alter, Krankheitsdauer, Ausdehnung der Zottenveränderungen und der extraintestinalen Manifestationen sehr variabel. Die klassische Form der Zöliakie mit chronischen Durchfällen, vorgewölbtem Abdomen, Appetitlosigkeit und Gedeihstörung (Malabsorption)—im Erwachsenenalter als Sprue bekannt—stellt nur die Spitze des "Eisbergs" dar. Daneben gibt es eine noch viel größere Zahl atypischer, oligosymptomatischer Fälle mit extraintestinalen Manifestationen (z. B. an der Haut, den Gelenken, dem Skelett und den Zähnen) und mit neurologischen Symptomen oder Infertilität und Aborten. Assoziationen zu Autoimmunerkrankungen (Typ-1-Diabetes, Thyreoiditis) und Chromosomenanomalien (Down- und Turner-Syndrom) sind bekannt. In der Differenzialdiagnose unklarer Krankheitsbilder muss die Zöliakie aufgrund der hohen Prävalenz viel häufiger in Betracht gezogen werden.

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Cholesterinesterspeicherkrankheit als Ursache einer Hepatomegalie im Kindesalter

Case report.

We present a 9,5-years-old boy who suffered from hepatomegaly with concomitant increase of liver enzymes (ALAT, ASAT, γGT), abdominal pain, and hypercholesterolemia since the age of 2. After years of extensive examinations in several children's hospitals and a total of five liver biopsies, a tentative diagnosis of cholesteryl ester storage disease (CESD) was made at the age of 7. Low enzymatic activity of human lysosomal acid lipase/cholesteryl ester hydrolase (hLAL) in the patient´s leukocytes confirmed the diagnosis.

Genetics.

To characterize the underlying mutations, the ten exons of the hLAL gene were amplified by the polymerase chain reaction and sequenced. The boy was found to be a compound heterozygote for two genetic defects, a Gly₂₄₅→Stop mutation in exon 7 and a Gly₂₉₀→Arg substitution encoded by exon 9.

Discussion.

Especially in young patients with hepatomegaly, CESD is a rare, but important differential diagnosis.     

Porocytosis: secretion from small and medium-diameter vesicles and vesicle arrays without membrane fusion

We have recently proposed a mechanism to describe secretion, a fundament process in all cells. That hypothesis, called porocytosis, embodies all available data, and encompasses both forms of secretion, i.e., vesicular and constitutive. The current accepted view of exocytotic secretion involves the physical fusion of vesicle- and plasma membranes. However, that hypothesized mechanism does not fit all available physiological data (Silver et al., 2001; Kriebel et al., 2001). Energetics of apposed lipid bilayers do not favor unfacilitated fusion. Calcium ion levels are elevated in microdomains at levels of 10(-4)-10(-3)M for 1 ms or less, with the calcium ions showing limited lateral mobility at the site of secretion (Llinas et al., 1992, Silver et al., 1994). We consider that calcium ions, whose mobility is restricted in space and time, establish "salt-bridges" among adjacent lipid molecules, and establishes transient pores that span the vesicle and plasma membrane lipid bilayers; the lifetime of that transient pore being completely dependent on duration of sufficient calcium ion levels.     

Dopamine D2 (DAD2) and dopamine D3 (DAD3) receptor gene polymorphisms and treatment outcome in alcohol dependence

Summary. The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of alcohol. The intention of this study was to investigate the genotypic frequencies of the −141C Ins/Del polymorphism of the DAD2 receptor gene as well as the Bal I polymorphism of the DAD3 receptor and their potential association with treatment outcome in alcoholism. Therefore, individuals suffering from primary alcohol dependence were clinically and genetically characterized and followed prospectively over a period of one year after inpatient treatment. No association was found between DAD2 or DAD3 receptor gene variants and treatment outcome as reflected by abstinence/relapse after one year. Taking into account potential stratification effects, such as family history, gender, age of onset, or severity of the disease an association with DAD2 or DAD3 gene variants could neither be found. In conclusion, we found no evidence that the DAD2 or DAD3 gene variants investigated have a major influence on treatment outcome in primary alcohol dependence. Received June 2002; accepted February 3, 2003 Published online April 22, 2003 RID="*" ID="*"  This paper is dedicated to Prof. Peter Riederer who celebrated his 60^th birthday in March 2002 Authors' address: PD Dr. G. A. Wiesbeck, Addiction Research Group, Psychiatric Clinic, University of Würzburg, Füchsleinstrasse 15, D-97080 Würzburg, Germany, e-mail: wiesbeck_g@klinik.uni-wuerzburg.de     

Suicide date and rates in a comparison of Germany, Bavaria and Upper Frankonia

The authors give an actual survey about suicides and suicide rates in Germany, Bavaria and Upper Frankonia. Their special interest are significant trends in the last years. These trends will be shown and shortly described.