Showing papers by "University of Duisburg-Essen published in 2008"

Sorafenib in Advanced Hepatocellular Carcinoma

Abstract: Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset

Abstract: Since the discovery of T helper type 1 and type 2 effector T cell subsets 20 years ago, inducible regulatory T cells and interleukin 17 (IL-17)-producing T helper cells have been added to the 'portfolio' of helper T cells. It is unclear how many more effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Here we show that transforming growth factor-beta, a cytokine at the center of the differentiation of IL-17-producing T helper cells and inducible regulatory T cells, 'reprograms' T helper type 2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drives the differentiation of 'T(H)-9' cells directly. Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways.

γ-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin

Abstract: DNA double-strand breaks (DSBs) are extremely dangerous lesions with severe consequences for cell survival and the maintenance of genomic stability. In higher eukaryotic cells, DSBs in chromatin promptly initiate the phosphorylation of the histone H2A variant, H2AX, at Serine 139 to generate gamma-H2AX. This phosphorylation event requires the activation of the phosphatidylinositol-3-OH-kinase-like family of protein kinases, DNA-PKcs, ATM, and ATR, and serves as a landing pad for the accumulation and retention of the central components of the signaling cascade initiated by DNA damage. Regions in chromatin with gamma-H2AX are conveniently detected by immunofluorescence microscopy and serve as beacons of DSBs. This has allowed the development of an assay that has proved particularly useful in the molecular analysis of the processing of DSBs. Here, we first review the role of gamma-H2AX in DNA damage response in the context of chromatin and discuss subsequently the use of this modification as a surrogate marker for mechanistic studies of DSB induction and processing. We conclude with a critical analysis of the strengths and weaknesses of the approach and present some interesting applications of the resulting methodology.

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Abstract: BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Impression Management 2.0. The Relationship of Self-Esteem, Extraversion, Self-Efficacy, and Self-Presentation Within Social Networking Sites.

Abstract: Investigated the relationship between self-reported (offline) personality traits and (online) self-presentation in social networking profiles on the Internet. Social networking sites like MySpace, Facebook, and StudiVZ are popular means of communicating personality. Recent theoretical and empirical considerations of homepages and Web 2.0 platforms show that impression management is a major motive for actively participating in social networking sites. 58 users (mean age 22.98 years) of the German Web 2.0 site, StudiVZ.net, completed online questionnaires assessing extraversion (NEO Personality Inventory, NEO-FFI), self-esteem (Rosenberg Self-Esteem Scale, RSES), and efficacy of self-presentation, and their profiles were subject to a content analysis. Findings reveal a slight influence of extraversion on self-presentation, whereas there was no significant effect for self-esteem. Moveover, analyses of respondents' profiles showed that self-efficacy with regard to impression management is strongly related to the number of virtual friends, the level of profile detail, and the style of the personal photo.

Telmisartan to prevent recurrent stroke and cardiovascular events.

Abstract: BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO.

Abstract: Summary of consensus a. All patients with GO should (Fig. 1):Be referred to specialist centers;Be encouraged to quit smoking;Receive prompt treatment in order to restore andmaintain euthyroidism.b. Patients with sight-threatening GO should be treatedwith i.v. GCs as the first-line treatment; if the responseis poor after 1–2 weeks, they should be submitted tourgent surgical decompression.c. The treatment of choice for moderate-to-severe GO isi.v. GCs (with or without OR) if the orbitopathy isactive;surgery(orbitaldecompression,squintsurgery,and/or eyelid surgery in this order) should beconsidered if the orbitopathy is inactive.d. In patients with mild GO, local measures and anexpectant strategy are sufficient in most cases, buttreatment may be justified if QoL is affectedsignificantly. In memoriam This document is dedicated to the memory of MarkPrummel (1956–2005), one of the founders ofEUGOGO, who greatly contributed to expanding ourunderstanding of clinical and therapeutic aspects of GO.

Inorganic Nanoparticles as Carriers of Nucleic Acids into Cells

Abstract: The transfer of nucleic acids (DNA or RNA) into living cells, that is, transfection, is a major technique in current biochemistry and molecular biology. This process permits the selective introduction of genetic material for protein synthesis as well as the selective inhibition of protein synthesis (antisense or gene silencing). As nucleic acids alone are not able to penetrate the cell wall, efficient carriers are needed. Besides viral, polymeric, and liposomal agents, inorganic nanoparticles are especially suitable for this purpose because they can be prepared and surface-functionalized in many different ways. Herein, the current state of the art is discussed from a chemical viewpoint. Advantages and disadvantages of the available methods are compared.

Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis

Abstract: Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr(-/-)Smpd1(+/-) mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.

Running: the risk of coronary events : Prevalence and prognostic relevance of coronary atherosclerosis in marathon runners.

Abstract: Aims To quantify the prevalence of coronary artery calcification (CAC) in relation to cardiovascular risk factors in marathon runners, and to study its role for myocardial damage and coronary events. Methods and results In 108 apparently healthy male marathon runners aged ≥50 years, with ≥5 marathon competitions during the previous three years, the running history, Framingham risk score (FRS), CAC, and presence of myocardial late gadolinium enhancement (LGE) were measured. Control groups were matched by age (8:1) and FRS (2:1) from the Heinz Nixdorf Recall Study. The FRS in marathon runners was lower than in age-matched controls (7 vs. 11%, P < 0.0001). However, the CAC distribution was similar in marathon runners and age-matched controls (median CAC: 36 vs. 38, P = 0.36) and higher in marathon runners than in FRS-matched controls (median CAC: 36 vs. 12, P = 0.02). CAC percentile values and number of marathons independently predicted the presence of LGE (prevalence = 12%) ( P = 0.02 for both). During follow-up after 21.3 ± 2.8 months, four runners with CAC ≥ 100 experienced coronary events. Event-free survival was inversely related to CAC burden ( P = 0.018). Conclusion Conventional cardiovascular risk stratification underestimates the CAC burden in presumably healthy marathon runners. As CAC burden and frequent marathon running seem to correlate with subclinical myocardial damage, an increased awareness of a potentially higher than anticipated coronary risk is warranted.

Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy.

Abstract: Luigi Bartalena, Lelio Baldeschi, Alison J. Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten P. Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Curro, Chantal Daumerie, George J. Kahaly, Gerasimos Krassas, Carol M. Lane, John H. Lazarus, Michele Marino, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, and Wilmar M. Wiersinga

Structural basis for the regulated protease and chaperone function of DegP

Abstract: All organisms have to monitor the folding state of cellular proteins precisely. The heat-shock protein DegP is a protein quality control factor in the bacterial envelope that is involved in eliminating misfolded proteins and in the biogenesis of outer-membrane proteins. Here we describe the molecular mechanisms underlying the regulated protease and chaperone function of DegP from Escherichia coli. We show that binding of misfolded proteins transforms hexameric DegP into large, catalytically active 12-meric and 24-meric multimers. A structural analysis of these particles revealed that DegP represents a protein packaging device whose central compartment is adaptable to the size and concentration of substrate. Moreover, the inner cavity serves antagonistic functions. Whereas the encapsulation of folded protomers of outer-membrane proteins is protective and might allow safe transit through the periplasm, misfolded proteins are eliminated in the molecular reaction chamber. Oligomer reassembly and concomitant activation on substrate binding may also be critical in regulating other HtrA proteases implicated in protein-folding diseases.

Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment.

Abstract: Liver failure is a dreaded and often fatal complication that sometimes follows a partial hepatic resection This article reviews the definition, incidence, pathogenesis, risk factors, risk assessment, prevention, clinical features and treatment of post-resectional liver failure (PLF) A systematic, computerized search was performed using key words related to 'partial hepatic resection' and 'liver failure' to review most relevant literature about PLF published in the last 20 years The reported incidence of PLF ranges between 07 and 91% An inadequate quantity or quality of residual liver mass are key events in its pathogenesis Major risk factors are the presence of comorbid conditions, pre-existent liver disease and small remnant liver volume (RLV) It is essential to identify these risk factors during the pre-operative assessment that includes evaluation of liver volume, anatomy and function Preventive measures should be applied whenever possible as curative treatment options for PLF are limited These preventive measures intend to increase RLV and protect remnant liver function Management principles focus on support of end-organ and liver function Further research is needed to elucidate the exact pathogenesis of PLF and to develop and validate adequate treatment options

CRLH metamaterial leaky-wave and resonant antennas

Abstract: Composite right-/left-handed (CRLH) transmission-line (TL) metamaterials, with their rich dispersion and fundamental right-/left-hand duality, represent a paradigm shift in electromagnetics engineering and, in particular, for antennas. This paper presents an overview of the most practical leaky-wave and resonant CRLH antennas, which all exhibit functionalities or/and performance superior to prior state of the art. The leaky-wave antennas provide full-space dynamic scanning capability, with fan beams, conical beams in uni-planar configurations, pencil beams without any complex feeding network, and actively shaped beams based on the concept of aperture digitization. The resonant antennas offer alternative properties and a solution to beam-squinting when no scanning is required, including multi-band (dual/tri-band) operation, zeroth-order high efficiency, high directivity, and planar electric and magnetic monopole radiators.

The relevance of shape and size of Au55 clusters

Abstract: This critical review deals with the history of Au55(PPh3)12Cl6 and its derivatives from the very beginning in 1981 to date. Au55 clusters obtain their special interest from their ultimate size and their ideal cuboctahedral structure. They are part of the family of so-called full-shell clusters, particles with perfectly completed geometries, also represented by icosahedral Au13 clusters. Bare as well as ligand protected Au55 clusters not only exhibit special chemical and physical stability, but draw their attention particularly from their unique electronic properties. Single electron switching at room temperature becomes possible, giving rise for development of applications in future nanoelectronic devices. A predominantly size-determined property of the 1.4 nm particles becomes obvious with respect of biological response. Au55 clusters indicate an unusual cytotoxicity which seems to be caused by the unusually strong interaction between the 1.4 nm particles and the major grooves of DNA. Only marginally smaller or larger particles show drastically reduced toxicity, whereas significantly larger gold nanoparticles are completely non-toxic. Both, the electronic perspectives as well as the relevance in toxicology are at very early stages of development (75 references).

Origin and pathogenesis of nodular lymphocyte–predominant Hodgkin lymphoma as revealed by global gene expression analysis

Abstract: The pathogenesis of nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) and its relationship to other lymphomas are largely unknown. This is partly because of the technical challenge of analyzing its rare neoplastic lymphocytic and histiocytic (L&H) cells, which are dispersed in an abundant nonneoplastic cellular microenvironment. We performed a genome-wide expression study of microdissected L&H lymphoma cells in comparison to normal and other malignant B cells that indicated a relationship of L&H cells to and/or that they originate from germinal center B cells at the transition to memory B cells. L&H cells show a surprisingly high similarity to the tumor cells of T cell–rich B cell lymphoma and classical Hodgkin lymphoma, a partial loss of their B cell phenotype, and deregulation of many apoptosis regulators and putative oncogenes. Importantly, L&H cells are characterized by constitutive nuclear factor κB activity and aberrant extracellular signal-regulated kinase signaling. Thus, these findings shed new light on the nature of L&H cells, reveal several novel pathogenetic mechanisms in NLPHL, and may help in differential diagnosis and lead to novel therapeutic strategies.

Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study

Abstract: Summary Background The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. Methods Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NTC00153062. Findings 20 332 patients (mean age 66 years) were randomised and followed-up for a median of 2·4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0·38), or with telmisartan versus placebo (p=0·61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups. Interpretation Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan. Funding Boehringer Ingelheim; Bayer-Schering Pharma (in selected countries); GlaxoSmithKline (in selected countries).

A journey to highly dynamic, self-adaptive service-based applications

Abstract: Future software systems will operate in a highly dynamic world. Systems will need to operate correctly despite of unespected changes in factors such as environmental conditions, user requirements, technology, legal regulations, and market opportunities. They will have to operate in a constantly evolving environment that includes people, content, electronic devices, and legacy systems. They will thus need the ability to continuously adapt themselves in an automated manner to react to those changes. To realize dynamic, self-adaptive systems, the service concept has emerged as a suitable abstraction mechanism. Together with the concept of the service-oriented architecture (SOA), this led to the development of technologies, standards, and methods to build service-based applications by flexibly aggregating individual services. This article discusses how those concepts came to be by taking two complementary viewpoints. On the one hand, it evaluates the progress in software technologies and methodologies that led to the service concept and SOA. On the other hand, it discusses how the evolution of the requirements, and in particular business goals, influenced the progress towards highly dynamic self-adaptive systems. Finally, based on a discussion of the current state of the art, this article points out the possible future evolution of the field.

A FTIR and 2D-IR Spectroscopic Study on the Microdynamics Phase Separation Mechanism of the Poly(N-isopropylacrylamide) Aqueous Solution

Abstract: The thermal behavior of PNIPAM in its concentrated D2O solution (20 wt %) was studied by FTIR and 2D-IR correlation spectroscopy. The spectral data of the C−H groups and the Amide I region provide details about the changes of the hydrophobic and hydrophilic parts in the polymer respectively during a heating−cooling cycle. The reversal of peak positions of the C−H bands upon cooling indicates the reversibility of temperature-induced dehydration of the hydrophobic groups. The change in hydrogen bonding of CO···D−N constructed between dehydrated CO and N−D groups, as derived from the Amide I region, does not revert precisely in the cooling process due to the newly formed hydrogen bonds in the collapsed state, and a hysteresis phenomenon is observed. In our concentrated solution (20 wt %), the strength of those intra- and interchain hydrogen bonds even prevent the polymers from dissociating completely below the LCST during the cooling process. The microdynamics phase separation mechanism was obtained by appli...

Response to Letter Regarding Article, “Residential Exposure to Traffic Is Associated With Coronary Atherosclerosis”

Abstract: We thank Dr Brook for his insightful comments and agree with his opinion that short-term effects are important mechanisms of particulate matter (PM) –related health effects. However, we do not agree that our study results represent a “minor” proatherosclerotic effect.1 The 7% higher coronary calcification score is related to a reduction in the distance between the residence and a major road by half. Therefore, it is not …

Dynamically assisted Schwinger mechanism.

Abstract: We study electron-positron pair creation from the Dirac vacuum induced by a strong and slowly varying electric field (Schwinger effect) which is superimposed by a weak and rapidly changing electromagnetic field (dynamical pair creation). In the subcritical regime where both mechanisms separately are strongly suppressed, their combined impact yields a pair creation rate which is dramatically enhanced. Intuitively speaking, the strong electric field lowers the threshold for dynamical particle creation--or, alternatively, the fast electromagnetic field generates additional seeds for the Schwinger mechanism. These findings could be relevant for planned ultrahigh intensity lasers.

Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum

Abstract: CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CASK mutations had congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation.