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1.  Everolimus and Early Calcineurin Inhibitor Withdrawal: 3-Year Results From a Randomized Trial in Liver Transplantation 
The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 postrandomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 postrandomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] −1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m2 (95% CI −0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m2 (95% CI −1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.
The beneficial effect on renal function achieved by early CNI withdrawal and treatment with everolimus after liver transplantation is still evident after three years.
doi:10.1111/ajt.12615
PMCID: PMC4285226  PMID: 24502384
Calcineurin inhibitor; everolimus; liver transplantation; long-term; withdrawal
2.  Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice 
Blood Cancer Journal  2014;4(8):e240-.
The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYKwt, TEL–SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYKwt enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK–SYK caused lethal T-cell lymphomas and the cytoplasmic TEL–SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL–SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL–SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL–SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases.
doi:10.1038/bcj.2014.53
PMCID: PMC4219468  PMID: 25148222
5.  Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease 
Neurology  2008;70(16 0 2):1456-1460.
Objective
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.
Methods
We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.
Results
The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30 –79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.
Conclusions
The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.
doi:10.1212/01.wnl.0000304044.22253.03
PMCID: PMC3906630  PMID: 18337586
6.  Neurological picture 
doi:10.1136/jnnp.2010.218313
PMCID: PMC3773517  PMID: 21217161
7.  Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model 
Blood Cancer Journal  2013;3(8):e131-.
Follicular lymphomas (FLs) account for 35–40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of the type II anti-CD20 MAb obinutuzumab (GA101) aims to further improve treatment. Here, using FL cells we show that RTX and GA101 display a similar activity on RL cells cultured in 2D. However, 2D culture cannot mimic tumor spatial organization and conventional 2D models may not reflect the effects of antibodies as they occur in vivo. Thus, we created a non-Hodgkin's lymphoma (NHL) 3D culture system, termed multicellular aggregates of lymphoma cells (MALC), and used it to compare RTX and GA101 activity. Our results show that both antibodies display greater activity towards FL cells in 3D culture compared with 2D culture. Moreover, we observed that in the 3D model GA101 was more effective than RTX both in inhibiting MALC growth through induction of (lysosomal) cell death and senescence and in inhibiting intracellular signaling pathways, such as mammalian target of rapamycin, Akt, PLCgamma (Phospholipase C gamma) and Syk. Altogether, our study demonstrates that spatial organization strongly influences the response to antibody treatment, supporting the use of 3D models for the testing of therapeutic agents in NHL.
doi:10.1038/bcj.2013.32
PMCID: PMC3763386  PMID: 23933705
spatial organization; monoclonal antibodies; follicular lymphoma; 3D model
8.  Molecular characterization of novel trispecific ErbB-cMet-IGF1R antibodies and their antigen-binding properties 
Therapeutic antibodies are well established drugs in diverse medical indications. Their success invigorates research on multi-specific antibodies in order to enhance drug efficacy by co-targeting of receptors and addressing key questions of emerging resistance mechanisms. Despite challenges in production, multi-specific antibodies are potentially more potent biologics for cancer therapy. However, so far only bispecific antibody formats have entered clinical phase testing. For future design of antibodies allowing even more targeting specificities, an understanding of the antigen-binding properties of such molecules is crucial. To this end, we have generated different IgG-like TriMAbs (trispecific, trivalent and tetravalent antibodies) directed against prominent cell surface antigens often deregulated in tumor biology. A combination of surface plasmon resonance and isothermal titration calorimetry techniques enables quantitative assessment of the antigen-binding properties of TriMAbs. We demonstrate that the kinetic profiles for the individual antigens are similar to the parental antibodies and all antigens can be bound simultaneously even in the presence of FcγRIIIa. Furthermore, cooperative binding of TriMAbs to their antigens was demonstrated. All antibodies are fully functional and inhibit receptor phosphorylation and cellular growth. TriMAbs are therefore ideal candidates for future applications in various therapeutic areas.
doi:10.1093/protein/gzs048
PMCID: PMC3449402  PMID: 22936109
ITC; receptor tyrosine kinase; SPR; therapeutic antibodies; trispecific antibodies
9.  Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip 
Gene expression patterns : GEP  2011;11(5-6):349-359.
During embryogenesis, the rhombic lip of the fourth ventricle is the germinal origin of a diverse collection of neuronal populations that ultimately reside in the brainstem and cerebellum. Rhombic lip neurogenesis requires the bHLH transcription factor Atoh1 (Math1), and commences shortly after neural tube closure (E9.5). Within the rhombomere 1 – isthmus region, the rhombic lip first produces brainstem and deep cerebellar neurons (E9.5-E12), followed by granule cell precursors after E12. While Atoh1 function is essential for all of these populations to be specified, the downstream genetic programs that confer specific properties to early and late born Atoh1 lineages are not well characterized. We have performed a comparative microarray analysis of gene expression within early and later born cohorts of Atoh1 expressing neural precursors purified from E14.5 embryos using a transgenic labeling strategy. We identify novel transcription factors, cell surface molecules, and cell cycle regulators within each pool of Atoh1 lineages that likely contribute to their distinct developmental trajectories and cell fates. In particular, our analysis reveals new insights into the genetic programs that regulate the specification and proliferation of granule cell precursors, the putative cell of origin for the majority of medulloblastomas.
doi:10.1016/j.gep.2011.03.007
PMCID: PMC3095718  PMID: 21440680
rhombic lip; Atoh1; Math1; cerebellum; neurogenesis; rhombomere 1
10.  TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies 
Neurology  2011;76(10):887-894.
Objective:
To improve understanding of TRPV4-associated axonal Charcot-Marie-Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism.
Methods:
A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca2+ channel analysis, and cell viability assay with or without channel blockade.
Results:
Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca2+ levels and reversible cell death by the TRPV channel antagonist, ruthenium red.
Conclusion:
TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis. Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important. The reversibility of cell death by channel blockade provides an attractive area of investigation in consideration of treatable axonal degeneration.
doi:10.1212/WNL.0b013e31820f2de3
PMCID: PMC3059145  PMID: 21288981
11.  Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers 
Neurology  2011;77(4):325-333.
Objectives:
Using a family study design, we describe the motor and nonmotor phenotype in probands with LRRK2 G2019S mutations and family members and compare these individuals to patients with idiopathic Parkinson disease (iPD) and unrelated controls.
Methods:
Probands with G2019S mutations and their first-degree relatives, subjects with iPD, and unrelated control subjects were identified from 4 movement disorders centers. All underwent neurologic examinations and tests of olfaction, color vision, anxiety, and depression inventories.
Results:
Tremor was more often a presenting feature among 25 individuals with LRRK2-associated PD than among 84 individuals with iPD. Subjects with LRRK2-PD had better olfactory identification compared with subjects with iPD, higher Beck Depression Inventory scores, and higher error scores on Farnsworth-Munsell 100-Hue test of color discrimination. Postural or action tremor was more common among 29 nonmanifesting mutation carriers compared with 53 noncarriers within the families. Nonparkinsonian family members had higher Unified Parkinson's Disease Rating Scale motor scores, more constipation, and worse color discrimination than controls, regardless of mutation status.
Conclusions:
Although tremor is a more common presenting feature of LRRK2-PD than iPD and some nonmotor features differed in degree, the phenotype is largely overlapping. Postural or action tremor may represent an early sign. Longitudinal evaluation of a large sample of nonmanifesting carriers will be required to describe any premotor phenotype that may allow early diagnosis.
doi:10.1212/WNL.0b013e318227042d
PMCID: PMC3140802  PMID: 21753163
12.  Meningococcal purpura fulminans in children. II: Late orthopedic sequelae management 
Background
Purpura fulminans is a rare and extremely severe infection, mostly due to Neisseria meningitidis. Nineteen patients were followed up immediately after the initial multivisceral failure in order to diagnose late-onset orthopedic sequelae. We report our experience with these 19 patients, in light of our medical follow-up protocol and surgical management.
Materials and methods
Nineteen patients were referred for acute purpura fulminans between 1987 and 2005 to our institution and followed up prospectively until the present. We collected information on all diagnosed orthopedic sequelae, all surgical procedures performed, and the actual orthopedic outcome.
Results
Fourteen patients developed at least one orthopedic sequel after a mean of 2 years delay, with a mean of 8.65 years follow-up (range 3–22 years). The most common presentation was lower limb physeal growth plate arrest in eight patients involving 18 growth plates, leading to five limb length discrepancies and 12 significant knee and/or ankle deviations. Patients were treated by completing epiphysiodesis in addition to limb lengthening and/or reaxation osteotomies, except for two patients, in which epiphysiolysis was performed. All outcomes are, to date, satisfactory, with both knee and ankle axes within the physiological range. Among the seven patients who underwent below-knee amputation, six needed stump revision because of skin conflict (4) or prosthetics misadaptation due to upper tibial varus (2). Regarding the upper limb, three patients presented with four cicatricial scar bands, one located on a ring finger, two at the first commissure, and one at the wrist (all were successfully treated by enlargement Z-plasties). Two patients developed hip avascular necrosis.
Conclusion
It is important for children diagnosed with meningococcal purpura fulminans to be followed up closely starting from the very beginning by a pediatric orthopedic surgeon. It ensures that late-onset orthopedic sequelae will be diagnosed early. In accordance to the literature, this study highlights the high rate of lower limb epiphysiodesis, above all other types of sequelae. This study reports a possible link between purpura fulminans and avascular necrosis of the hip.
doi:10.1007/s11832-010-0285-3
PMCID: PMC2946529  PMID: 21966304
Purpura fulminans; Late-onset sequelae; Hip avascular necrosis
13.  Gaucher Disease Ascertained through a Parkinson’s Center: Imaging and Clinical Characterization 
Among the genes implicated for parkinsonism is glucocerebrosidase (GBA), which causes Gaucher disease (GD). Despite a growing literature that GD may present as parkinsonism, neuroimaging, olfaction and neuropsychological testing have not been extensively reported. We describe transcranial sonography (TCS), 18F-fluorodopa (F DOPA) and fluorodeoxyglucose (FDG) PET, olfaction testing, neuropsychological testing and clinical features in homozygous and compound heterozygous glucocerebrosidase mutation carriers identified through screening of 250 Ashkenazi Jewish parkinsonian individuals treated at a tertiary care center. We identified two individuals with N370S/R496H compound heterozygous mutations and two with N370S homozygous mutations; one individual died before completing detailed evaluation. TCS (n=3) demonstrated nigral hyperechogenicity that was greater than controls (median area maximal substantia nigra echogenicity (aSNmax) =0.28 cm2 vs. 0.14 cm2, p=0.005), but similar to IPD (aSNmax= 0.31 cm2). FDG PET (n=2) demonstrated hypermetabolism of the lentiform nuclei, and F-fluorodopa PET (n=2), bilateral reduction in striatal FDOPA uptake. Olfaction was markedly impaired in the two tested cases, including onset of smell disturbance in adolescence in one. Neuropsychological features (n=3) were consistent with Parkinson’s disease (PD) or diffuse Lewy body disease (DLB). The imaging, neuropsychological and olfactory markers suggest the GD phenotype includes PD with and without features of DLB, marked olfactory loss, nigral hyperechogenicity on TCS, and FDOPA and FDG PET abnormalities.
doi:10.1002/mds.23046
PMCID: PMC2914177  PMID: 20629126
Parkinson’s disease; Gaucher Disease; Glucocerebrosidase Mutations; Transcranial sonography; Functional Imaging; Olfaction
15.  Etiology of musician’s dystonia 
Neurology  2009;72(14):1248-1254.
Objective:
To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician’s dystonia (MD) and to identify possible environmental triggers.
Methods:
The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia [FTSD] and 14 with no known family history [FH−]) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD.
Results:
A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias: n = 2), 5 of whom were members of FH− families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members.
Conclusion:
Our results suggest a genetic contribution to musician’s dystonia with phenotypic variability including focal task-specific dystonia.
GLOSSARY
= Beth Israel Dystonia Screen;
= reported positive family history of focal task-specific dystonia;
= no known family history of focal task-specific dystonia;
= focal task-specific dystonia;
= musician’s dystonia;
= writer’s cramp.
doi:10.1212/01.wnl.0000345670.63363.d1
PMCID: PMC2677486  PMID: 19349605
16.  Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype 
Neurology  2009;72(12):1041-1047.
Objective:
To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.
Methods:
Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.
Results:
Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation.
Conclusion:
Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a “generic” compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.
GLOSSARY
= blood oxygen level–dependent;
= cingulate motor area;
= false discovery rate;
= functional MRI;
= hemodynamic response function;
= intraparietal sulcus;
= primary motor hand area;
= Parkinson disease;
= dorsal premotor cortex;
= supplementary motor area;
= statistical parametric mapping;
= small volume correction;
= echo time;
= transcranial magnetic stimulation;
= repetition time;
= volumes of interest.
doi:10.1212/01.wnl.0000338699.56379.11
PMCID: PMC2821837  PMID: 19038850
17.  Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden 
Autosomal recessive severe congenital neutropenia (SCN) or Kostmann syndrome is characterised by reduced neutrophil counts and subsequent recurrent bacterial infections. The disease was originally described in a large consanguineous pedigree from Northern Sweden. A genome-wide autozygosity scan was initiated on samples from four individuals in the original pedigree using high density single nucleotide polymorphism (SNP) genotyping arrays in order to map the disease locus. Thirty candidate regions were identified and the ascertainment of samples from two additional patients confirmed a single haplotype with significant association to the disorder (p<0.01) on chromosome 1q22. One affected individual from the original Kostmann pedigree was confirmed as a phenocopy. The minimal haplotype shared by affected individuals spans a candidate region of 1.2 Mb, containing several potential candidate genes.
doi:10.1016/j.bbrc.2006.12.086
PMCID: PMC2721957  PMID: 17188649
Kostmann syndrome; severe congenital neutropenia; SNP array; homozygosity mapping
18.  Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis 
Background
Mutations of myelin protein zero (MPZ) may cause inherited neuropathy with variable expression.
Objective
To report phenotypic variability in a large American kindred with MPZ mutation His39Pro.
Patients
Genetic testing was performed on 77 family members and 200 controls. Clinical and electrophysiological field study assessments were available for review in 47 family members.
Results
His39Pro was found in all 10 individuals prospectively identified with neuropathy. 200 normal controls were without mutation. Symptoms of neuropathy began in adulthood and were slowly progressive except for one acute-onset painful sensory neuropathy. Associated features included premature hearing loss (n  =  7), nocturnal restless leg symptoms (n = 8) and multiple sclerosis in one.
Conclusions
MPZ mutation His39Pro may be associated with acute-onset neuropathy, early‐onset hearing loss and restless legs. The relationship with multiple sclerosis in the proband remains uncertain.
doi:10.1136/jnnp.2006.090076
PMCID: PMC2077629  PMID: 16844954
19.  Haplotypes and gene expression implicate the MAPT region for Parkinson disease 
Neurology  2008;71(1):28-34.
Background
Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum.
Methods
Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR.
Results
After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT.
Conclusions
This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.
doi:10.1212/01.wnl.0000304051.01650.23
PMCID: PMC2654275  PMID: 18509094
20.  Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency 
Background
Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l‐dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms.
Objective
To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families.
Methods
GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed.
Results
Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late‐presenting mild dopa‐responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive‐compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l‐dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients.
Conclusion
Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.
doi:10.1136/jnnp.2004.051664
PMCID: PMC2117403  PMID: 16361586
GTP cyclohydrolase deficiency; major depression; phenotype; Segawa syndrome
21.  Dobutamine stress cardiovascular magnetic resonance at 3 Tesla 
Purpose
The assessment of inducible wall motion abnormalities during high-dose dobutamine-stress cardiovascular magnetic resonance (DCMR) is well established for the identification of myocardial ischemia at 1.5 Tesla. Its feasibility at higher field strengths has not been reported. The present study was performed to prospectively determine the feasibility and diagnostic accuracy of DCMR at 3 Tesla for depicting hemodynamically significant coronary artery stenosis (≥ 50% diameter stenosis) in patients with suspected or known coronary artery disease (CAD).
Materials and methods
Thirty consecutive patients (6 women) (66 ± 9.3 years) were scheduled for DCMR between January and May 2007 for detection of coronary artery disease. Patients were examined with a Philips Achieva 3 Tesla system (Philips Healthcare, Best, The Netherlands), using a spoiled gradient echo cine sequence. Technical parameters were: spatial resolution 2 × 2 × 8 mm3, 30 heart phases, spoiled gradient echo TR/TE: 4.5/2.6 msec, flip angle 15°. Images were acquired at rest and stress in accordance with a standardized high-dose dobutamine-atropine protocol during short breath-holds in three short and three long-axis views. Dobutamine was administered using a standard protocol (10 μg increments every 3 minutes up to 40 μg dobutamine/kg body weight/minute plus atropine if required to reach target heart rate). The study protocol included administration of 0.1 mmol/kg/body weight Gd-DTPA before the cine images at rest were acquired to improve the image quality. The examination was terminated if new or worsening wall-motion abnormalities or chest pain occurred or when > 85% of age-predicted maximum heart rate was reached. Myocardial ischemia was defined as new onset of wall-motion abnormality in at least one segment. In addition, late gadolinium enhancement (LGE) was performed. Images were evaluated by two blinded readers. Diagnostic accuracy was determined with coronary angiography as the reference standard. Image quality and wall-motion at rest and maximum stress level were evaluated using a four-point scale.
Results
In 27 patients DCMR was performed successfully, no patient had to be excluded due to insufficient image quality. Twenty-two patients were examined by coronary angiography, which depicted significant stenosis in 68.2% of the patients. Patient-based sensitivity and specificity were 80.0% and 85.7% respectively and accuracy was 81.8%. Interobserver variability for assessment of wall motion abnormalities was 88% (κ = 0.760; p < 0.0001). Negative and positive predictive values were 66.7% and 92.3%, respectively. No significant differences in average image quality at rest versus stress for short or long-axis cine images were found.
Conclusion
High-dose DCMR at 3T is feasible and an accurate method to depict significant coronary artery stenosis in patients with suspected or known CAD.
doi:10.1186/1532-429X-10-44
PMCID: PMC2572055  PMID: 18844984
22.  Cardiac magnetic resonance imaging: long term reproducibility of the late enhancement signal in patients with chronic coronary artery disease 
Heart  2005;91(9):1158-1163.
Objective: To determine long term reproducibility of the late enhancement (LE) signal in contrast enhanced magnetic resonance imaging (MRI) and potential changes of the signal after revascularisation.
Methods: 33 patients (29 men, mean (SD) 61 (11) years) with coronary artery disease (CAD) and left ventricular dysfunction (ejection fraction 30 (7)%) underwent two contrast enhanced MRI procedures within 9 (3) months. Fifteen patients (group A: 14 men, 59 (12) years) had no interventions between the two studies. Eighteen patients underwent revascularisation after MRI 1 (group B: 15 men, 62 (9) years). Changes in the LE signal between the first and second MRIs were investigated in both groups as well as intraobserver and interobserver variabilities for delineation of the signal.
Results: The LE signal was highly reproducible in groups A and B for segmental analysis (concordance 86% v 82%, respectively; κ  =  0.70 v 0.67) and summed scores (group A: r  =  0.97, p < 0.001; group B: r  =  0.93, p < 0.001). The LE signal was quantified as 27 (27) cm3 in group A versus 30 (16) cm3 in group B in the first MRI and 26 (25) cm3 versus 30 (15) cm3, respectively, for the second MRI (both not significant). Moreover, low intraobserver and interobserver variabilities were observed in segmental analysis (κ  =  0.86 and 0.74, respectively, for group A, and κ  =  0.87 and 0.82, respectively, for group B).
Conclusion: In patients with chronic CAD, the LE signal in contrast enhanced MRI is very stable over an extended time period. These results further characterise contrast enhanced MRI as a useful tool for myocardial viability assessment. Low intraobserver and interobserver variabilities promise robustness of the method for clinical application.
doi:10.1136/hrt.2004.045609
PMCID: PMC1769072  PMID: 16103547
magnetic resonance imaging; contrast media; coronary artery disease; heart failure
23.  Detection of Mycoplasma hyopneumoniae by polymerase chain reaction in swine presenting respiratory problems 
Brazilian Journal of Microbiology  2008;39(3):471-476.
Since Mycoplasma hyopneumoniae isolation in appropriate media is a difficult task and impractical for daily routine diagnostics, Nested-PCR (N-PCR) techniques are currently used to improve the direct diagnostic sensitivity of Swine Enzootic Pneumonia. In a first experiment, this paper describes a N-PCR technique optimization based on three variables: different sampling sites, sample transport media, and DNA extraction methods, using eight pigs. Based on the optimization results, a second experiment was conducted for testing validity using 40 animals. In conclusion, the obtained results of the N-PCR optimization and validation allow us to recommend this test as a routine monitoring diagnostic method for Mycoplasma hyopneumoniae infection in swine herds.
doi:10.1590/S1517-838220080003000011
PMCID: PMC3768421  PMID: 24031248
Swine Enzootic Pneumonia; Mycoplasma hyopneumoniae; diagnosis; Nested- PCR
24.  SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies 
Objective: To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7.
Patients: DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients with idiopathic sensory neuropathy were also screened for known mutations of these genes.
Results: Of the 25 kindreds, only one had a mutation (SPTLC1 399T→G). This kindred, and 10 without identified mutations, had prominent mutilating foot injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity with injuries but no weakness, one had restless legs and burning feet, and one had dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neuropathy.
Conclusions: Adult onset HSAN I is clinically and genetically heterogeneous and further work is required to identify additional genetic causes. Known SPTLC1or RAB7 mutations were not found in idiopathic sensory neuropathy.
doi:10.1136/jnnp.2004.050062
PMCID: PMC1739730  PMID: 15965219

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